eBook

The Role ofReal-World Evidencein FDA Approvals
2021 UPDATEDID YOU KNOW?

78%

of FDA-approved NDAs
and BLAs in 2020 included
an RWE study to provide
evidence of safety and/or
effectiveness.
As industry prepares for additional guidance from FDA on the useof real-world evidence (RWE), Aetion conducted a systematic reviewof FDA approval documents to understand the role RWE can play toand how RWE studies influenced the 2020 approvals of New Drug
Applications (NDAs) and Biologics License Applications (BLAs).

Global biopharma organizations, leading payers, andregulatory and health technology assessment bodies use
Aetion Evidence Platform® to generate decision-grade RWE.
Read on to learn how Aetion can help you advance yourRWE strategy.

aetion.com

This 2021 update of our eBook will guide you through when, where,

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inform regulatory decisions.

2

CONTENTS
How RWE studies are usedin FDA approvals

Analysis acrosstherapeutic areas

How RWE studies informprescribing

Deep dive: Key components ofa successful external control arm

Learnings from external control arms
with study design limitations

Generate decision-grade
RWE with Aetion

1aetion.com

In 2019, 53 percent of
FDA-approved NDAs
and BLAs included an
RWE study to provide
evidence of safety
and/or effectiveness.
In 2020, that figure
jumped to 78 percent.

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HOW RWE STUDIES AREUSED IN FDA APPROVALS4

In 74 percent of the approvals that
included an RWE study in 2020, theRWE influenced FDA’s approval decision.
From 2019 to 2020, the use of RWE in submission packages to FDA increased
substantially, and RWE continues to provide evidence of safety and/or effectivenessin a growing number of regulatory decisions.
The overall increase in RWE studies submitted to FDA may help inform future RWE
guidance

How RWE studies informed FDA decisions 2
SUBSTANTIAL OR PRIMARY EVIDENCE
9%SUPPORTIVE EVIDENCE
65%
59%
NOT ADEQUATE FOR DECISION-MAKING
9%22%

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11%

17%
7%
2020 (n= 46 approvals)

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2019 (n= 27 approvals)

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RWE STUDIES THAT FDA DID NOT ADDRESS

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ANALYSIS ACROSSTHERAPEUTIC AREAS

2020 FDA approvals that included
RWE studies span 10 therapeutic areas.
20
19
18
—
12
11
10
9
8
7

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6
5
4
3
2
1
0

Total
approvals

Infectious
diseaseNeuroscience

Approvals with 
an RWE study

Endocrinology
& metabolism

Radiology

Dermatology

GastroRWE study deemed substantial/primaryevidence and/or supportive evidence

Ophthalmology (representing 3 approvals) did not have any RWE submissions.

Anesthesiology

Urology

Allergy

RWE study and/or findings
referenced in the package insert

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Oncology

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ANALYSIS ACROSS THERAPEUTIC AREAS

Infectious disease
In 2020, all eight approvals in infectious disease included an RWE study in the approval
documents, and six of them provided substantial, primary, or supportive evidence.
Additionally, six of the RWE studies submitted were mentioned in the product label.
Products approved to treat infectious diseases are often first approved in other markets
where there’s a greater disease burden. This may contribute to the notable use of RWE
in approvals, as applicants can use data generated from the real-world usage of theseinterventions to generate RWE that supports new product approvals.
We share a closer look into a selection of the RWE-supported approvals for infectious
disease interventions:

FDA’S DECISION ON
THE RWE STUDY/STUDIESRWE

ARTESUNATE(for injection)

Bayer

LAMPIT®
(nifurtimox)

Gilead Sciences

VEKLURY®
(remdesivir)

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

Substantial
or primaryevidence

Supportive
evidence

Not adequate
for decisionmaking

Referenced in
product label













Safety &Effectiveness

Safety &Effectiveness








Safety &Effectivenesssales@aetion.com

AmivasSubmitted
in support ofaetion.com

Manufacturer/
Product

Included in
FDA-definedsafetypopulation

RWE

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ANALYSIS ACROSS THERAPEUTIC AREAS

Oncology
Of the 20 oncology approvals in 2020, 18 included an RWE study. Of those, 61 percent of thestudies provided substantial or supportive evidence—a sizable increase from 2019, where just
25 percent of submitted RWE studies supported the product’s approval.
We share a closer look into a selection of the RWE-supported oncology approvals:

FDA’S DECISION ON
THE RWE STUDY/STUDIESRWEManufacturer/
Product

Submitted
in support of

Included in
FDA-definedsafetypopulation

Substantial
or primaryevidence

Supportive
evidence

RWE

Not adequate
for decisionmaking

Referenced in
product label

GlaxoSmithKline(belantamab
mafodotin-blmf)

EffectivenessMorphoSys US Inc.

MONJUVI®

Safety(tafasitamab-cxix)

EpizymeTAZVERIK®



Safety &Effectiveness

aetion.com(tazemetostat)

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59 percent of decisions’subsequent product labels
refer to RWE studies andtheir findings.

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HOW RWE STUDIESINFORM PRESCRIBING

9

It’s now becoming routine to see RWE studies
and findings cited in the product labels of
FDA-approved drugs and biologics.
See how FDA referenced an RWE study in the product label
for VEKLURY® (remdesivir).

On October 22, 2020, FDA
approved Gilead Sciences’s
VEKLURY, a treatment for COVID-19
in hospitalized patients 12 yearsof age and older. In addition to theclinical trial evidence that provided
the applicant also included

Excerpt from the EUA Fact Sheetemergency use authorization (EUA)

for Healthcare Providers referring

data, and four additional studies
to provide additional evidence ofsafety and efficacy.
FDA referenced RWE studies
and findings from the EUA andcompassionate use program
data alongside clinical trial
results in VEKLURY’s fullprescribing information.

to the RWE studies:“The safety of VEKLURY isbased on data from three
Phase 3 studies in 1,313
hospitalized adult subjects
with COVID-19, from fourPhase 1 studies in 131 healthy
adults, and from patientswith COVID-19 who received
VEKLURY under the Emergency
Use Authorization or in acompassionate use program.”

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data, compassionate use program

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substantial evidence of efficacy,

10DEEP DIVE: KEY COMPONENTS OFA SUCCESSFUL EXTERNALCONTROL ARM

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EVRYSDI™ (risdiplam) for
spinal muscular atrophy

11DEEP DIVE: EVRYSDI™ (RISDIPLAM)

External control arms (ECAs)
generated from RWD can serve
as viable controls for single-arm
trials when conducted at thehighest levels of scientific rigor.
In the case of Genentech’s EVRYSDI (risdiplam), an ECA composed of several
natural history studies provided substantial evidence of effectiveness.4
FDA approved EVRYSDI on August 7, 2020, to treat spinal muscular atrophy (SMA)
in infants two months of age and older.

Intent of the RWE study
The applicant referenced multiple published natural history studies as abenchmark for comparison to the FIREFISH trial, a phase 2/3 open-label, singlearm trial. The primary objective of these studies was to demonstrate that patientswith Type 1 SMA are never able to sit without support. The secondary objective
was to show the rates of survival and ventilator-free survival. The applicant also
referenced natural history studies as context for baseline scores of the Children’s
Hospital of Philadelphia Infant Test of Neuromuscular Disorders, known as CHOPINTEND score. CHOP-INTEND uses a zero-to-64-point scoring scale, in which

Protocols for RWE generation
While FDA at first expressed preference for a placebo control for FIREFISH—citing
concerns around bias and differences in study populations in the RWE arm—it
eventually agreed to the single-arm trial, with conditions. To demonstrate efficacy,
the single-arm trial had to show that at least five out of 40 patients could sit
without support, and the applicant had to “provide data that supports thesales@aetion.com

higher scores indicate better motor function.

this milestone as defined by the protocol.”To construct the ECA, the applicant relied on several natural history studies toserve as contextual controls for the primary and secondary endpoints, as well as
to inform the CHOP-INTEND baseline score.
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assertion that untreated children essentially never would be expected to reach12

DEEP DIVE: EVRYSDI™ (RISDIPLAM)
Protocols for RWE generation continued
To support the primary endpoint and demonstrate that patients with Type 1
SMA are never able to sit without support, the applicant submitted five studies:“Further evidence of the benefit

Finkel et al. 2014a; Finkel et al. 2015; Faravelli et al. 2015; De Sanctis et al. 2016;of risdiplam in treating infants

and Kolb et al. 2017.

with Type 1 SMA was provided

For the secondary endpoints of survival and ventilation-free survival, theapplicant submitted an additional five studies: Finkel et al. 2014b, Kolb et al. 2017,
Oskoui et al. 2007, Rudnik-Schöeneborn et al. 2009, and and CARNIVAL Type 1,
a phase 1/2 study.

by an open-label, historicallycontrolled, multicenter study
that showed improvements
in multiple clinical functional
measures compared to the

To provide context for the trial participants’ CHOP-INTEND baseline scores, theapplicant submitted four studies: Darras 2016; De Sanctis et al. 2016;
De Sanctis et al. 2017, and Kolb et al. 2017.

Outcome of the RWE study
The RWE studies provided substantial evidence of effectiveness to support theapproval of EVRYSDI. FDA stated that the natural history ECA “showed improvements in multiple clinical functional measures compared to the natural history of
SMA, including motor function and developmental milestones as well as survival

natural history of SMA. This
study provides evidenceof reduced mortality andpermanent ventilation in therisdiplam group comparedto the natural history ofType 1 SMA.”
FDA’S CLINICAL REVIEW

and ventilation-free survival.”
When discussing the primary endpoint of the FIREFISH experimental arm comparedto the natural history studies, FDA’s biometrics review concluded “the evidence from
FIREFISH ... is not well controlled.” However, the clinical reviewer came to a different
conclusion, stating it “considers the external natural history control as sufficient todescribe the FIREFISH study as ‘well-controlled’ because no Type 1 SMA patients
disease.” FDA also noted that the threshold of five patients sitting without support
was previously agreed upon by FDA and the applicant before the study initiation,and stated that such an endpoint was “well-defined with a low potential for bias.”
For the secondary endpoint of ventilation-free survival, 94 percent of the higher
dose cohort in FIREFISH was alive after 12 months. FDA concluded that “the FIREFISH
Part 1 study result indicates reduced mortality and permanent ventilation in thesales@aetion.com

would be expected to achieve sitting without support in the natural history of theThis study also showed a four point increase in CHOP-INTEND score in 88 percent of
the higher dose cohort—an improvement in motor function never before seen in twoof the natural history studies. 53 percent of the participants in this cohort alsoachieved head control, compared to 39 percent achieving partial head control inaetion.com

risdiplam group compared to the natural history of Type 1 SMA.”

the De Sanctis study.
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DEEP DIVE: EVRYSDI™ (RISDIPLAM)

5

REASONS
why risdiplam represents a good
opportunity for the use of an ECA

1

2

3

Well-defined natural history

Objective endpoint

Patient comparability

The natural progression of

The criteria that made up the

While there has been some

SMA is well understood.

“favorable outcome” endpoint—therapeutic innovation in thesitting without support andpast few years, historical data are

ventilation-free survival—are both

expected to be of good quality.

objectively verifiable endpoints,

Historic subtype classification

though they may not be evident in

may be problematic.

5

Good covariate
measurement

Larger effect size

The covariate measurement was

be able to sit without support, it isexpected to be sufficient, though

clear that the effect size is large

subject to certain limitations.

and easily measurable.

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Since no patients with SMA would

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traditionally structured data sources.

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There is much to learn
from applications with
an RWE study that FDA
deemed not adequate
for decision-making, andfrom the reasoning behindthe determination.
By understanding the reasoning behind
FDA’s decision, applicants can design
RWE studies that more closely align withevidentiary requirements. This can also help

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LEARNINGS FROM EXTERNALCONTROL ARMS WITH STUDYDESIGN LIMITATIONS

in an RWE study being rejected or not consideredas part of FDA’s decision.

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them avoid common pitfalls that may result

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LEARNINGS FROM EXTERNAL CONTROL ARMS WITH STUDY DESIGN LIMITATIONS

Common methodological issues with ECAs 5,6“Due to major methodological issues (including immortal time bias, selection
bias, misclassification, confounding, and missing data), FDA did not consider
RWD adequate to support regulatory decision making.”

XPOVIO®
(selinexor)BALVERSA™
(erdafitinib)

ROZLYTREK®
(entrectinib)

TAZVERIK™
(tazemetostat)

Confounding bias









Selection bias









Post-hoc analysis



Limited cohort sizeData missingnessImmortal time bias

Lack of transparency









“The protocol for the natural history study does not provide adequate detailsales@aetion.com

FDA’S MULTI-DISCIPLINE REVIEW

choices, rendering the results of the study uninterpretable.”FDA’S ADMINISTRATIVE AND CORRESPONDENCE DOCUMENTS

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regarding quality of data, validity of endpoint assessments, and design

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LEARNINGS FROM EXTERNAL CONTROL ARMS WITH STUDY DESIGN LIMITATIONS

How can you design ECAs
that support regulatory
decision-making?
There are several actions applicants can take to rectify
common missteps in RWE studies, including:Integrated planning

Eligibility criteria

Design the experimental study

Apply the same selection criteria

and the ECA together,to both the experimental andfrom the beginning.

external control arms. Creating
an ECA that is a true counterfactual
to the clinical trial is the only way
to establish causality.

Trial sites and data
Work with trial sites to explore
external control availability,
calibrate data, and build

Early and frequentevidence to meet success criteria.

regulator engagement
Meet proactively with FDA toTarget trial emulation
Think of the RWD study as arandomized controlled trial, andmimic aspects of the “target

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align on study design.

protocol, and analysis phases toensure confounding control.

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trial” across the design,

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GENERATE DECISION-GRADE
RWE WITH AETION“Aetion Evidence Platform has been tremendous
for us with regards to delivering RWE more efficiently.
From an operational perspective, it has helped us
generate high quality evidence faster, and allows

aetion.com

DR. BOB LOCASALE
Head of RWE, Sanofi

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us to deliver more for our stakeholders.”

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Rapid, reliable answers

Standard-setting partner

Data fluent and independentthat reviewers trust

Aetion partners with FDA, ICER, NICE,

AEP can ingest any data from any

Conduct regulatory-grade studies

and other global regulators andsource, in native or common datawith speed, while maintaining thehealth technology assessment bodies

model formats. Our data scientists

highest level of scientific accuracy.

on initiatives that set standards andand epidemiologists help identify

AEP enables stakeholder alignmentbuild confidence in the use of RWE. For

the RWD sources best suited for yourby providing transparent reporting,example, FDA selected Aetion for astudy. The platform provides overaudit trails, and the ability for

research collaboration to advance

1,500 pre-built, customizable clinicalreviewers to rerun analyses.

the understanding of COVID-19. We

definitions (“measures”) that allow

also serve as a partner on the RCT

users to work with any data source

DUPLICATE demonstration project.

in a traceable, reproducible way.

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COVID Drug Treatment Pathways

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Use Aetion
Evidence Platform®
(AEP) to generate
decision-readyevidence at scale
for regulatory,
policy, and pricing
decisions—anywhere scientificrigor matters most.

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Work with Aetion toadvance your RWE strategy.
Learn more at aetion.com
or contact sales@aetion.com.

Aetion delivers real-world evidence for the manufacturers, purchasers,
and regulators of medical treatments and technologies. The Aetion Evidence
Platform® analyzes data from the real world to produce transparent, rapid, andscientifically validated answers on safety, effectiveness, and value. Foundedby Harvard Medical School faculty members with decades of experience inepidemiology and health outcomes research, Aetion informs health care’s
most critical decisions—what works best, for whom, and when—to guide
product development, commercialization, and payment innovation.
Aetion is based in New York City and backed by investors including New
Enterprise Associates (NEA), Warburg Pincus, Flare Capital Partners, Greenspring
Associates, Lakestar, B Capital, Foresite Capital, Town Hall Ventures, McKesson
Ventures, Sanofi Ventures, EDBI, Johnson & Johnson Innovation—JJDC, Inc., UCB,
Amgen Ventures, and Horizon Health Services, Inc. Learn more at aetion.com
and follow us at @aetioninc.

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Endnotes
1. 	Of the 161 FDA-approved NDAs and BLAs in 2019, we analyzed 51. Of the 147 FDA-approved NDAs and BLAs in 2020, we analyzed 59.
Our analyses included approvals defined by FDA’s classification guide as NDA Type 1 (New Molecular Entities, or NMEs) and Type 9(“new indication or claim, drug not to be marketed under Type 9 NDA after approval”), as these are the core mechanisms for FDA toconsider marketing authorization for new molecules. We excluded the remainder of FDA’s NDA classifications, meaning non-NME
approvals, assays, blood grouping reagents, and solutions. Note that applications that are not approved by FDA are not available
for public consumption, and therefore not reflected in our analysis.
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2. Substantial or primary evidence: Evidence which makes the primary case for product safety and/or effectiveness is referred to as“substantial evidence” by FDA’s Center for Drug Evaluation and Research, and as “primary evidence” by FDA’s Center for Biologics
Evaluation and Research. According to FDA, “evidence consisting of adequate and well-controlled investigations, including clinicalinvestigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on thebasis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or isrepresented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labelingthereof.”Supportive evidence: A manufacturer submitted RWE studies that don’t serve as the primary basis for FDA’s approval decision, butthat pertain to the safety or effectiveness of a drug or biologic.
Not adequate for decision-making: A manufacturer included an RWE study to establish or support product safety and/or
effectiveness, but FDA could not conclude as such. The RWE study does not inform the agency’s decision-making.
RWE studies that FDA did not address: A manufacturer included an RWE study to support product safety and/or effectiveness, but
FDA did not speak to the study and/or there is no evidence that the study informed the agency’s decision-making.
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3. 	Applications containing RWE studies that are considered substantial or supportive evidence of product safety and/or effectivenessfeature the RWE studies or findings in the product label 59 percent of the time; this reflects 20 out of 34 applications.
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4. 	Honig N, Louder A. “CDER-Approved NDA for EVRYSDI™ (risdiplam),” FDA Decision Alerts, Aetion, December 17, 2020.
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5. 	Oztop I, et al. Review Of Oncology Real-world Comparator Arm Submissions In Support Of Effectiveness Claims In 2019 FDA
Original Approvals Reveals Label-grade Real-world Study Best Practices. 2020 ICPE All Access On Demand.
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6. 	Purpura C, Patrick A. “CDER-Approved NDA for TAZVERIK™ (tazemetostat),” FDA Decision Alerts, Aetion, August 14, 2020.
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Updated as of October 2021.