SCIENCE science.org 3 DECEMBER 2021 • VOL 374 ISSUE 6572 1207awareness and burden, as well as economic
challenges about who should pay for treat-
ment use of investigational drugs ( 12 ).
FINANCIAL GATEKEEPING
In contrast to other countries, where drug
approval is often followed by national deci-
sions about whether to pay for those drugs,
US payment decisions rarely diverge from
FDA approvals. For Aduhelm, however,
several prominent hospital systems have
declined to use the drug, and major payers
have hesitated to extend coverage or an-
nounced restrictive conditions for payment.
US laws and insurance contracts already
allow payers to exercise restraint on cover-
ing products that lack evidence of clinical
benefit. However, some American payers
have a “pass through” mentality, in which
they lack incentives to meaningfully police
the value of products and services that they
reimburse. In the short run, saying “yes”
minimizes public relations problems raised
by sympathetic patients, even if it inflates
government-subsidized insurance premi-
ums and national debt in the long run.
Saying “no” is harder.
The solution here may be to reconceive
coverage decisions as more-or-less, rather
than yes-or-no. The Center for Medicare and
Medicaid Services has authority to imple-
ment “coverage with evidence development”
(CED), whereby it covers items or services
only for patients participating in a clinical
study or registry, a process currently being
considered for Aduhelm. However, to date,
CED has been infrequently used and rarely
involves prospective randomized controlled
trials. More generally, a government mandate
for scaled reimbursement or adjusting re-
bates based on the quality of evidence could
create incentives both for drugmakers to de-
velop rigorous evidence and for patients to
enroll in trials.
EVIDENCE-BASED POLICY
Continued acceptance of early approval path-
ways should be based on evidence regarding
whether, when, and how meaningful post-
approval trials will be possible. As the US
Department of Health and Human Services
Office of the Inspector General (OIG) under-
takes its review of the accelerated approval
pathway, we recommend that it prioritize
generation of this evidence.
One approach OIG should consider is ex-
amining the details of trials that have further
evaluated a drug’s approved indication after
marketing approval, looking to distinguish
the features of trials that were more versus
less successful. Several reviews have studied
postmarket trials, providing valuable insight
on broad characteristics such as study type,
indication, and population; trial size, dura-
tion, and endpoints; use of randomization,
blinding, and comparator groups; and trial
registration, completion, and results report-
ing (4, 5, 13–15). However, other essential
questions have received far less attention
but may be relevant to the conditions under
which patients are willing to enroll and trials
able to complete. How serious and fast-mov-
ing is the disease? Are there other approved
products for that indication? What were the
target recruitment numbers compared to fi-
nal enrollment? How many sites participated
in the trial and how accessible were those
sites? Were sites international? Was placebo
used? What was the randomization ratio?
Were participants given the opportunity to
cross over from control to intervention? Were
any financial incentives offered? It could also
be valuable to examine the perspectives of
patients, company executives, and regulators
through qualitative methods such as inter-
views ( 7 ) and focus groups about how best to
encourage rigor, enrollment, and completion
of these studies, as well as the barriers and
disincentives to doing so. Important patternsmay emerge from this type of analysis that
could help inform both drugmakers and FDA
when deciding how to design postmarket
trials and whether to grant early approval
based on their likely feasibility.
Accelerated approval is an important regu-
latory pathway worth trying to save, if the
evidence suggests that meaningful improve-
ments in confirmatory trials are possible.
While this evidence is gathered, companies,
patients, and policy-makers should prioritize
efforts to meaningfully improve access to in-
vestigational products in the preapproval pe-
riod, without further pushing the boundaries
of accelerated approval. jREFERENCES AND NOTES- J. D. Wallach, R. Ramachandran, T. Bruckner, J. S. Ross,
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- Institute for Clinical and Economic Review,
“Strengthening the FDA’s Accelerated Approval
Pathway” (2021); https://icer.org/assessment/
fda-accelerated-approval-pathway/. - H. Naci, K. R. Smalley, A. S. Kesselheim, JAMA 318 , 626
(2017). - B. Gyawali, S. P. Hey, A. S. Kesselheim, JAMA Intern. Med.
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information/search-fda-guidance-documents/
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ACKNOWLEDGMENTS
The authors are members of the NYU Grossman School
of Medicine Division of Medical Ethics Working Group on
Compassionate Use and Preapproval Access (CUPA).
10.1126/science.abk3495FOOD AND DRUG
ADMINISTRATION FDA DRUGMAKERS PAT I E N TS PAY E RSPreapproval • Demand proof of safety
and effectiveness (and access
to underlying data) to meet
statutory approval standards
- Consider patient and political
pressure for access to
products with potential
clinical benefit- Perform minimum necessary studies
(size, length, endpoints) to support FDA
approval and payer reimbursement - Develop relationships with patients
and FDA to support rapid approval
to maximize intellectual property
protections and profit- Seek rapid access to potentially
life-saving products, including through
participation in randomized, placebo-
controlled trials, if necessary - In some cases, push for early approval
with later confirmation of benefit - May receive drugmaker support for
advocacy organizations- Refuse to pay for “experimental”
products
- Refuse to pay for “experimental”
- Seek rapid access to potentially
- Perform minimum necessary studies
Postapproval • Face political barriers to
enforcement action, including
withdrawing approval,
especially absent alternative
therapies, even if benefit is not
confirmed
- Maximize return on investment through
high prices and efforts to encourage use - Avoid trials that could raise questions
about approved indication;
have low incentive for rigor or speed - Pursue studies to support sales,
especially for off-label indications- Pursue approved, reimbursed
therapeutic options over participation
in randomized trials - May receive funds from drugmakers
for advocacy and to cover access
costs, if other payers are unavailable
or decline- Cover “medically necessary” care,
typically aligned with FDA approval - Can pursue mechanisms to avoid or
limit coverage of high-priced products
supported by weak evidence, but
constrained by political, legal, and
market pressures
- Cover “medically necessary” care,
- Pursue approved, reimbursed
Typical interests and influences of key stakeholders before and after approval of a new drug