SCIENCE science.org 3 DECEMBER 2021 • VOL 374 ISSUE 6572 1205By Holly Fernandez Lynch^1 and
Christopher T. Robertson^2I
t’s easy to understand the urge to make
potentially beneficial drugs quickly
available to patients in need. It’s also
easy to go too far. Through its 2021 ap-
proval of Aduhelm (aducanumab) for
treatment of Alzheimer’s disease, the
US Food and Drug Administration (FDA)
showed a willingness to embrace early ap-
proval pathways in ways that risk FDA’s
reputation and undermine its core role in
keeping the market free of worthless or
dangerous medical products. Early approval
pathways are intended to strike a careful
compromise: access to promising therapies
today, confirmatory evidence tomorrow.
However, this often results in access—often
at a hefty cost—accompanied by a persistent
lack of evidence of benefit. To improve the
balance between access and proof, we must
understand why postapproval studies often
flounder. Is it due to insufficient incentives
for companies to pursue rigorous trials af-
ter approval, disincentives for patients to
enroll in them, or both?
To guide policy-makers in capturing the
promise of early approval and to inform
assessment of newly proposed pathways
favored by some patient groups, we recom-
mend careful empirical assessment of what
is currently inhibiting postapproval studies
and what could make them more successful.EARLY APPROVAL PATHWAYS
Traditional FDA approval requires “sub-
stantial evidence” of effectiveness, typically
through a demonstration of clinical benefit
in how patients feel, function, or survive—
or at least improvement on a validated sur-
rogate endpoint. By contrast, the emergency
use authorization (EUA) pathway used
widely during COVID-19 allows temporary
marketing on the basis that a product “maybe effective,” a weaker standard and one
with mixed success (contrast problematic
hydroxychloroquine and highly effective
COVID-19 vaccines). Fortunately, EUAs ter-
minate with the end of the public health
emergency, returning companies to the
baseline requirement to prove safety and
effectiveness before further market access.
Another early approval pathway, accel-
erated approval, allows effectiveness to be
demonstrated through reliance on unvali-
dated surrogate endpoints deemed “rea-
sonably likely to predict clinical benefit.”
Accelerated approval drugs like Aduhelm
can be marketed without special restrictions,
but in return for accepting uncertainty at the
outset, these approvals are paired with a re-
quirement for postmarket study to confirm
predicted benefit. The European Medicines
Agency (EMA) offers a similar “conditional
approval” pathway that relies on a limited
clinical data package, followed by “specific
obligations” for postmarket study.ACCESS BEFORE EVIDENCE
Reliance on future confirmatory evidence is
perilous for several reasons. First, confirma-
tory evidence may be long delayed. A recent
study found a median time of 50 months
from accelerated approval to the deadlines
FDA set for sponsors to report postmarket
trial results, a median of 30 months more
than the duration of the trials themselves
once launched ( 1 ). Earlier studies note sub-
stantial delays in starting postmarket trials,
as well as concern about early termination
( 2 ). The Institute for Clinical and Economic
Review (ICER) found that of 145 accelerated
approvals predating 2016, 13% have not yet
produced evidence to support transition to
full approval (or withdrawal), despite being
on the market for a median of 9.5 years ( 3 ).
For Aduhelm, FDA gave the sponsor 9 years
to submit the final report for its confirma-
tory trial, details of which have not yet been
settled. In another controversial example,
FDA granted accelerated approval to Ex-
ondys 51 (eteplirsen) for Duchenne muscu-
lar dystrophy in 2016, but the confirmatorytrial is not slated to end until 2026, after a
3-year delay in initiation. Most EMA post-
marketing obligations after conditional ap-
proval are also delayed.
Second, studies following accelerated ap-
proval often lack rigorous design charac-
teristics, such as blinding, randomization,
and concurrent controls. In addition, they
sometimes continue to rely on surrogate
endpoints (4, 5), rather than clinical out-
comes, with the same being true in Europe.
As a result, even confirmatory trials and full
approval may not ensure that a drug will
meaningfully improve patient health (3, 6).
Third, unlike EMA’s conditional approv-
als, which must be renewed annually until
specific obligations are fulfilled, FDA’s ac-
celerated approvals are not time limited.
Moreover, failure to meet postapproval re-
quirements or confirm benefit does not nec-
essarily lead to enforcement action, such as
fines or speedy withdrawal ( 3 , 6 , 7 ). Instead,
FDA has discretion about how to proceed,
potentially granting extensions or calling
for more studies. For example, upon find-
ing 10 “dangling approvals” whose required
trials did not confirm benefit, sponsors
voluntarily withdrew four indications, but
FDA’s advisory committee recommended
withdrawal for only two of the remaining
six ( 8 ). Especially when alternatives are
lacking, FDA may be convinced that some-
thing is better than nothing, allowing even
questionable drugs to remain on the market
( 7 ). Even if FDA recommends withdrawal,
sponsors can push back through lengthy ad-
ministrative proceedings.WHAT’S STANDING IN THE WAY?
These shortcomings in producing and act-
ing upon postapproval evidence—which
have been attributed to insufficient re-
sources and legal authority at FDA, as
well as “the prevailing political economy”
of pressure from Congress, patients, and
companies ( 7 )—raise questions about the
balance sought by early approval pathways
( 9 ). One of the most critical is whether it
is truly feasible to produce adequate, high-
quality confirmatory evidence reasonably
quickly once a product has been allowed on
the market (see the table).It’s the companies
Companies may fail to produce rigorous
postmarket evidence because FDA is not
forcing them to do so—and Congress has
not forced FDA. Because FDA’s gatekeep-
ing authority allows it to exclude new drugs
from the market until their safety and ef-
fectiveness have been demonstrated, in the
preapproval period companies have strong
incentives to produce that evidence as
quickly as possible. Moreover, FDA’s author-RESEARCH AND REGULATIONChallenges in confirming drug
effectiveness after early approval
Reform requires clarity about whether, when,
and how meaningful postapproval trials are possible
POLICY FORUM
(^1) University of Pennsylvania, Philadelphia, PA, USA.
(^2) Boston University, Boston, MA, USA.
Email: [email protected]