Research

JAMA | Original Investigation

Associations Between Surrogate Markers and Clinical Outcomes

for Nononcologic Chronic Disease Treatments
Joshua D. Wallach, PhD, MS; Samuel Yoon, BS, BA; Harry Doernberg, MM; Laura R. Glick, MD; Oriana Ciani, PhD;
Rod S. Taylor, PhD; Maryam Mooghali, MD; Reshma Ramachandran, MD, MHS, MPP; Joseph S. Ross, MD, MHS

Supplemental content
IMPORTANCE Surrogate markers are increasingly used as primary end points in clinical trials
supporting drug approvals.

OBJECTIVE To systematically summarize the evidence from meta-analyses, systematic

reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials
examining the strength of association between treatment effects measured using surrogate
markers and clinical outcomes in nononcologic chronic diseases.
DATA SOURCES The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and
MEDLINE from inception to March 19, 2023.

STUDY SELECTION Three reviewers selected meta-analyses of clinical trials; meta-analyses of

observational studies were excluded.

DATA EXTRACTION AND SYNTHESIS Two reviewers extracted correlation coefficients,

coefficients of determination, slopes, effect estimates, or results from meta-regression
analyses between surrogate markers and clinical outcomes.

MAIN OUTCOMES AND MEASURES Correlation coefficient or coefficient of determination,

when reported, was classified as high strength (r ⱖ 0.85 or R2 ⱖ 0.72); primary findings were
otherwise summarized.

RESULTS Thirty-seven surrogate markers listed in FDA’s table and used as primary
end points in clinical trials across 32 unique nononcologic chronic diseases were included.
For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was
identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis
was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these,
median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056
(IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate
marker–clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported
at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates,
or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically
significant result.

CONCLUSIONS AND RELEVANCE Most surrogate markers used as primary end points in clinical
trials to support FDA approval of drugs treating nononcologic chronic diseases lacked
high-strength evidence of associations with clinical outcomes from published meta-analyses.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Joshua D.
Wallach, PhD, MS, Department of
Epidemiology, Rollins School of Public
Health, Emory University, 1518 Clifton
JAMA. doi:10.1001/jama.2024.4175 Rd, Room 3033, Atlanta, GA 30322
Published online April 22, 2024. (joshua.wallach@emory.edu).

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 Research Original Investigation Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments
C
linical trials increasingly use surrogate markers, such
as imaging findings or laboratory measurements, as pri-
mary end points.1-3 Surrogate markers, which are ex-
pected to predict target outcomes of interest (eg, clinical out-
comes that directly measure how people feel, function, or
survive),4 offer the advantage of reducing the duration, size,
and total cost of trials.5,6 In 2018, the Food and Drug Admin-
istration (FDA) publicly released an Adult Surrogate End-
point Table of more than 100 surrogate markers that may be
used as primary end points in clinical trials that form the ba-
sis of traditional or accelerated approval of new drugs or bio-
logics. Although this table was designed to serve as a refer-
ence for drug developers, it does not provide justification for
surrogate selection in terms of strength of evidence of asso-
ciations between the treatment effects measured using the sur-
rogate marker and those measured using disease-relevant clini-
cal outcomes.
In oncology, surrogate markers, such as progression-free
survival and objective response rate, are weakly associated with
clinical outcomes such as overall survival and quality of life.7-10
However, to our knowledge, no studies have examined such
associations for surrogate markers used as primary end points
in clinical trials to support FDA approval of drugs treating non-
oncologic chronic diseases, which compose one-third of dis-
ease indications listed in FDA’s table. Accordingly, our objec-
tive was to systematically review the literature to identify and
summarize all meta-analyses of clinical trials examining the
strength of association between treatment effects measured
using surrogate markers listed in FDA’s Adult Surrogate End-
point Table and those measured using any clinical outcomes
for nononcologic chronic diseases. We focused on published
meta-analyses as opposed to independently meta-analyzing
clinical trial data because FDA has maintained that the use of
surrogate markers in traditional approval requires, at a mini-
mum, evidence from meta-analyses of clinical trials demon-
strating an association between surrogate markers and clini-
cal outcomes to establish surrogacy.11
Methods
This review, prospectively registered on OSF.io, is reported in
accordance with Preferred Reporting Items for Systematic Re-
views and Meta-analyses (PRISMA) guidelines. Institutional
review board approval and participant informed consent were
not required for this review because it used only previously
published research.
Surrogate Marker Selection
On August 2, 2022, we reviewed FDA’s Adult Surrogate End-
point Table12 to identify all surrogate markers that may be used
as primary end points in clinical trials to support FDA approval
of drugs treating chronic diseases (Figure 1; eMethods in Supple-
ment 1). We did not consider FDA’s Pediatric Surrogate End-
point Table and excluded any surrogate markers for diseases
listed in FDA’s Adult Surrogate Endpoint Table that were acute
illnesses (eg, skin infection), primarily genetic (eg, Fabry dis-
ease, cystic fibrosis), oncology related,9,10 or vaccine related.
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Key Points
Question What is the strength of association between surrogate
markers used as primary end points in clinical trials to support
Food and Drug Administration (FDA) approval of drugs treating
nononcologic chronic diseases and clinical outcomes?
Findings No meta-analyses of clinical trials examining the
strength of association between treatment effects measured using
surrogate markers and clinical outcomes were identified for 22
(59%) of 37 surrogate markers for 32 chronic diseases, whereas at
least 1 was identified for 15 (41%), although few reported
high-strength evidence of treatment effect associations.
Meaning Most surrogate markers used as primary end points in
clinical trials to support FDA approval of drugs treating
nononcologic chronic diseases lack high-strength evidence of
associations with clinical outcomes from published meta-analyses.
Data Sources and Selection
For each surrogate marker, we conducted independent system-
atic reviews for English-language meta-analyses of clinical trials
through searches of MEDLINE (Ovid ALL) from inception to
March 19, 2023, using broad study design (eg, meta-analyses),
correlation, surrogate marker, and chronic disease–specific
terminology (eMethods in Supplement 1). Reference lists of
eligible studies were reviewed manually.
Study Selection
Three reviewers (J.D.W., S.Y., and L.R.G.) independently
screened titles and abstracts. Full-text versions of potentially
eligible articles were subsequently reviewed to identify sum-
mary or individual patient-level data meta-analyses, system-
atic reviews and meta-analyses, and pooled analyses (hereaf-
ter, meta-analyses) of clinical trials. Meta-analyses were eligible
if they (1) reported summary measures of associations, includ-
ing correlation coefficients, coefficients of determination,
slopes, effect estimates, results from meta-regression analy-
ses, or any other metrics of association or prediction (eg, sur-
rogate threshold effect13) for the association between treat-
ment effects measured using the surrogate marker and any
clinical outcome (ie, surrogate marker–clinical outcome
pairs)12; and (2) included at least 1 component study in which
the disease, patient population, and medication(s) were the
same as described in FDA’s table. We excluded pooled analy-
ses containing only 2 component studies, meta-analyses con-
taining observational studies, earlier versions of updated meta-
analyses, and meta-analyses evaluating only individual patient-
level correlations (ie, they did not examine changes attributable
to treatment) (eMethods in Supplement 1).
Data Extraction
For each eligible meta-analysis, 3 reviewers (J.D.W., S.Y., and
H.D.) recorded study characteristics and identified all corre-
lation coefficients or coefficients of determination (eMethods
in Supplement 1). If none were reported, we abstracted slopes
and effect estimates from regression-based analyses or other
metrics of association or prediction. Last, we recorded the au-
thors’ subjective interpretation of the association between each
surrogate marker–clinical outcome pair.
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 Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments
Data Synthesis and Analysis
For each surrogate marker–clinical outcome pair, the number
of correlation coefficients, coefficients of determination,
slopes, effect estimates, or results from meta-regression analy-
ses that were statistically significant (P < .05) was identified.
Correlation coefficients or coefficients of determination were
then classified as providing high-strength evidence accord-
ing to criteria proposed by the Institute for Quality and Effi-
ciency in Health Care (r ≥ 0.85 or R2 ≥ 0.72).14 For meta-
analyses reporting inconsistent evidence across multiple
associations for the same surrogate marker–clinical outcome
pair (eg, high- and low-strength correlations across different
subgroups or follow-up durations), the evidence was classi-
fied as mixed. Descriptive statistics were calculated to char-
acterize the eligible meta-analyses and evidence examining the
strength of association between surrogate markers and clini-
cal outcomes with RStudio (Posit) and R (R Foundation for
Statistical Computing).
Results
Study Characteristics
There were 37 surrogate markers listed in FDA’s Adult Surro-
gate Endpoint Table that may be used as primary end points
for clinical trials of 32 unique nononcologic chronic diseases
(7 for accelerated approval and 30 for traditional approval)
(Table; eMethods in Supplement 1). For these 37 surrogate
markers, 31 independent systematic reviews were conducted
because the table contained similar diseases (eg, Cushing dis-
ease and Cushing syndrome) and some surrogate markers were
listed multiple times. Overall, 19 993 records were identified
for title and abstract screening (median, 216 records; range,
3-5541) (Figure 2; eFigures 1-31 in Supplement 1).
For 22 of the 37 surrogate markers (59%) that may be used
as primary end points for 21 chronic diseases, no eligible meta-
analysis of clinical trials quantifying the strength of associa-
tion between the treatment effects measured using the rel-
evant surrogate marker and any clinical outcome was identified
(Table; eFigures 1-17 in Supplement 1). Of these surrogate mark-
ers, 17 (77%) were classified by FDA as being appropriate for
traditional approval, including forced expiratory volume in the
first second of expiration (FEV1) for asthma and urine toxicol-
ogy for opioid use disorder, and 5 (23%) as being appropriate
for accelerated approval.
For 15 of the 37 surrogate markers (41%) that may be used
as primary end points for 14 chronic diseases (Table), at least
1 meta-analysis of clinical trials was identified, totaling 54
unique meta-analyses (median, 2.5; IQR, 1.3-6.0). Of these sur-
rogate markers, 13 (87%) were classified by FDA as being ap-
propriate for traditional approval and 2 (13%) for accelerated
approval. The median number of trials and patients meta-
analyzed in these 54 meta-analyses was 18.5 (IQR, 12.0-43.0)
and 90 056 (IQR, 20 109-170 014), respectively.
The 54 meta-analyses, 14 (26%) of which had any indus-
try funding, reported 200 total associations for 109 unique
surrogate marker–clinical outcome pairs (Figure 3; eTable 1A
and B in Supplement 1). At least 1 correlation coefficient
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Original Investigation Research
Figure 1. Surrogate Marker Selection Flowchart
197 Total adult and pediatric disease surrogate end point
pairs in FDA's table of surrogate end points
73 Pediatric disease surrogate
end point pairs excludeda
124 Total adult disease surrogate end point pairs
87 Disease surrogate end point
pairs excluded
24 Primarily genetic
23 Vaccine related
20 Cancer indications
18 Acute conditions
2 Dental illness
37 Total surrogate markers for 32 unique chronic diseases
FDA indicates Food and Drug Administration.
a
The FDA has a separate Pediatric Surrogate Endpoint Table.
or coefficient of determination was reported for 59 (54%)
surrogate marker–clinical outcome pairs, 10 (17%) of which
reported at least 1 that provided high-strength evidence
(ie, r ≥ 0.85 or R 2 ≥ 0.72). The remaining 50 pairs (46%)
reported only slopes, effect estimates, results from meta-
regression analyses, or another metric of association or pre-
diction, 26 (52%) of which reported at least 1 statistically sig-
nificant result.
Surrogate Markers That May Be Used
for Accelerated Approval
Alzheimer Disease Surrogate Marker: Amyloid-β Plaque Deposition
Of 792 records screened, 3 meta-analyses offered inconsis-
tent evidence on the strength of association between reduc-
tion in amyloid-β plaque deposition and several cognitive rat-
ing scales for Alzheimer disease (eTable 2 and eFigure 18 in
Supplement 1). One reported low-strength correlation coeffi-
cients between reductions in amyloid-β deposition and changes
in the Clinical Dementia Rating Scale sum of boxes (Pearson
r = 0.51; P = .09 [n = 9 randomized clinical trials {RCTs}]) and
Alzheimer’s Disease Assessment Scale–Cognitive subscale
(Pearson r=0.68; P = .02 [n = 9 RCTs]),15 whereas another re-
ported that a decrease in amyloid-β level detected by posi-
tron emission tomography of 0.1 standardized uptake value
ratio unit was not associated with a reduction in the Clinical
Dementia Rating Scale sum of boxes score (0.051 point;
95% CI, −0.027 to 0.13 [n = 10 RCTs]) or the Mini Mental State
Examination score (0.087 point; 95% CI, −0.042 to 0.22 [n = 14
RCTs]).16 However, a third reported that a 0.1-unit decrease in
amyloid-β level detected by positron emission tomography was
associated with statistically significant decreased reductions
in the Clinical Dementia Rating Scale sum of boxes score (0.09
point; 95% CI, 0.03-0.15 [n = 15 RCTs]), Mini Mental State Ex-
amination score (0.13 point; 95% CI, 0.017-0.24 [n = 16 RCTs]),
and Alzheimer’s Disease Assessment Scale–Cognitive score
(0.33 point; 95% CI, 0.12-0.55 [n = 15 RCTs]).17
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 Research Original Investigation Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Table. Surrogate Markers for Nononcologic Chronic Disease Treatments Table. Surrogate Markers for Nononcologic Chronic Disease Treatments
in the FDA’s Adult Surrogate Endpoint Table in the FDA’s Adult Surrogate Endpoint Table (continued)

Disease or use Patient population Surrogate end point Disease or use Patient population Surrogate end point
Surrogate markers appropriate for accelerated approval with at least 1 Cushing disease Patients with Cushing Urine free cortisol level
a
meta-analysis of clinical trials disease for whom
Alzheimer disease Patients with mild Reduction in amyloid-β pituitary surgery is not an
cognitive impairment or plaques option or has not been
mild dementia stage of curative
Alzheimer disease Cushing syndrome Patients with endogenous
Primary glomerular Patients with primary Proteinuria (urinary Cushing syndrome who
diseases associated glomerular disease protein to creatinine have type 2 diabetes
with significant associated with ratio) mellitus or glucose
proteinuria significant proteinuria intolerance and have
failed surgery or are not
Surrogate markers appropriate for accelerated approval without any
candidates for surgery
meta-analyses of clinical trialsa
Exocrine pancreatic Patients with exocrine Fecal coefficient of fat
HDV Patients with HDV ≥2 Log reduction in HDV
insufficiency pancreatic insufficiency absorption
infection with or without RNA plus normalization
due to cystic fibrosis
cirrhosis of ALT
HDV below the LLOQb HBV Patients with HBV Undetectable plasma
infection with or without HBV DNA for indefinite
MAC lung disease Patients with MAC lung Sputum culture
cirrhosis treatment
disease conversion to negative
result by 6 mo HBsAg loss for finite
treatment
NASH Patients without cirrhosis Histopathologic findings
with NASH liver fibrosis of (1) resolution of HCV Patients with HCV Sustained viral response
steatohepatitis with no infection with or without (HCV RNA)
worsening of fibrosis, cirrhosis
or (2) improvement of HIV-1 Patients at high risk of Serum HIV antibody
fibrosis with no sexually acquired HIV-1 >0.5 Log reduction in
worsening of
plasma HIV RNA
steatohepatitis,
or (3) bothc Hypothyroidism Patients with Serum TSH level
hypothyroidism
Primary biliary Patients with primary Serum alkaline
cholangitis biliary cholangitis phosphatase and bilirubin Lupus nephritis Patients with active lupus CRR, defined as
nephritis (1) a response in the
Pulmonary Patients with active Sputum culture
urine proteinuria
tuberculosis pulmonary tuberculosis conversion to negative
level (protein to
result
creatine ratio);
Surrogate markers appropriate for traditional approval with at least 1 and (2) preservation or
meta-analysis of clinical trials improvement of kidney
Chronic kidney Patients with chronic Estimated glomerular function (estimated
disease kidney disease secondary filtration rate glomerular filtration
to multiple etiologies rate)
COPD Patients with COPD FEV1 Opioid use disorder Patients with opioid use Urine toxicology test
disorder result for opioids
Gout Patients with gout Serum uric acid level
Osteoporosis Postmenopausal women New morphometric
HIV-1 Patients with HIV-1 Undetectable plasma HIV with osteoporosis vertebral fractures
RNA
Paget disease Patients with Paget Serum alkaline
Hypercholesterolemia Patients with Serum low-density disease phosphatase level
heterozygous familial and lipoprotein cholesterol
nonfamilial level Primary Patients with Serum calcium level
hypercholesterolemia hyperthyroidism hypercalcemia
due to primary
Hyperphosphatemia Patients with Serum phosphate level hyperparathyroidism
hyperphosphatemia and
receiving dialysis Systemic Patients with systemic FVC
sclerosis–interstitial sclerosis–interstitial lung
Hypertension Patients with Systolic blood pressure lung disease disease
hypertension Diastolic blood pressure Tobacco dependence Cigarette smokers Exhaled carbon
Hypertriglyceridemia Patients with severe Serum triglyceride level monoxide level
hypertriglyceridemia
Abbreviations: ALT, alanine transaminase; COPD, chronic obstructive
Osteoporosis Patients with Bone mineral density pulmonary disease; CRR, complete renal response; FDA, Food and Drug
glucocorticoid-induced
osteoporosis Administration; FEV1, forced expiratory volume in 1 second; FVC, forced vital
Men with osteoporosis capacity; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus;
HCV, hepatitis C virus; HDV, hepatitis D virus; iPTH, intact parathyroid hormone;
Pulmonary fibrosis Patients with pulmonary FVC
LLOQ, lower limit of quantification; MAC, Mycobacterium avium complex;
fibrosis
NASH, nonalcoholic steatohepatitis; TSH, thyroid-stimulating hormone.
Secondary Patients with secondary Serum iPTH level
a
hyperparathyroidism hyperparathyroidism Measuring the strength of association between the relevant surrogate marker
associated with associated with chronic and clinical outcomes. Surrogate markers appropriate for accelerated approval
chronic kidney kidney disease and traditional approval are mutually exclusive.
disease
b
Type 2 diabetes Patients with type 2 Serum hemoglobin A1c The agency anticipates that this surrogate end point could be appropriate for
mellitus diabetes mellitus level use as a primary efficacy clinical trial end point for drug or biologic approval,
Surrogate markers appropriate for traditional approval without any although it has not yet been used to support an approved new drug
meta-analysis of clinical trialsa application or biologics license application.
Asthma Patients with asthma FEV1 c
Surrogate end point is part of a composite of biomarker surrogate end points.
Chronic kidney Patients with chronic Serum creatinine level
disease kidney disease secondary
to multiple etiologies Primary Glomerular Disease Surrogate Marker: Proteinuria
Of 19 records screened, 1 meta-analysis offered high-strength
(continued)
evidence of the association between proteinuria and the

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 Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments Original Investigation Research

composite end point of doubling of serum creatinine level, end-

Figure 2. Study Flowchart
stage kidney disease, or death (R2 = 0.91; 95% bayesian cred-
ible interval, 0.47-1.00 [n = 11 RCTs]) (eTable 3 and eFigure 19
22 197 Records included for 31 searches conducted in the
in Supplement 1).18 MEDLINE database, covering 37 disease surrogate
end point pairsa
18 Citation searches
Surrogate Markers That May Be Used
for Traditional Approval 2104 Duplicate references removed
Chronic Kidney Disease Surrogate Marker:
Estimated Glomerular Filtration Rate 19 993 Studies screened at the title and abstract level
Of 731 records screened, 2 meta-analyses offered consistent
evidence on the strength of association between reductions 19 561 Ineligible studies excluded at
in estimated glomerular filtration rate and a range of clinical the title and abstract level

outcomes (eTable 4 and eFigure 20 in Supplement 1). One

reported a high-strength coefficient of determination 432 Studies sought for retrieval and assessed for eligibility

between estimated glomerular filtration rate and the com-

posite end point of doubling of serum creatine level, esti- 374 Studies excluded
102 Wrong aim
mated glomerular filtration rate less than 15 mL/min/m2, 78 Observational or cohort studies only
and treated end-stage kidney disease (R2 = 0.97; 95% bayes- 50 Wrong surrogate end point
30 Wrong disease indication
ian credible interval, 0.78-1.00 [n = 47 RCTs]),19 whereas 30 Wrong study design
another reported that 30% and 40% reductions in esti- 24 Wrong or no clinical outcome
22 No discussion of association
mated glomerular filtration rate were associated with statis-
16 Systematic review only
tically significant improvements in treated end-stage kidney 10 Non-English language
disease.20 6 Overlapping with included article
2 Fewer than 3 included studies
2 Article not available
Chronic Obstructive Pulmonary Disease Surrogate Marker: FEV1 2 Abstract only

Of 569 records screened, 6 meta-analyses offered inconsis-

tent evidence on the strength of association between 54 Studies included in review,b with 109 associations
for surrogate marker–clinical outcome pairs
improvements in FEV1 and several objective and subjective 11 Hypercholesterolemia
clinical outcomes across different subgroups and follow-up 10 Hypertension
9 Type 2 diabetes
durations (ie, exacerbation rate, rescue medication use, 6 Chronic obstructive pulmonary disease
St George’s Respiratory Questionnaire, Transition Dyspnea 6 Osteoporosis
3 Alzheimer disease
Index, and risk for hospitalization) (eTable 5 and eFigure 21 3 Hypertriglyceridemia
in Supplement 1) and only reported 2 or more high-strength 2 Chronic kidney disease
coefficients of determination between change in trough 2 Gout
2 HIV
FEV1 and first occurrence of a moderate to severe exacerba- 1 Hyperphosphatemia
tion across all trials (R2 = 0.85) and among those evaluating 1 Primary glomerular disease
1 Pulmonary fibrosis
only bronchodilators (R2 = 0.88).21
a
eFigures 1 through 31 in Supplement 1 provide flowcharts for the individual
Gout Surrogate Marker: Serum Uric Acid chronic diseases.
Of 188 records screened, 2 meta-analyses offered inconsis- b
Four meta-analyses were applicable to 2 disease indications.
tent evidence on the strength of association between serum
uric acid and various clinical outcomes (eTable 6 and eFig-
ure 22 in Supplement 1). One reported a low-strength associa- load less than 200 copies/mL and progression to AIDS or
tion between achieving serum urate level less than 6 mg/dL death at 48 weeks (R2 = 0.86; P = .02 [n = 5 RCTs]) and 8
and the risk of patients’ experiencing gout flair (R2 = 0.0779 low-strength correlations for different viral load levels and
[n = 10 RCTs]),22 whereas another reported statistically sig- follow-up durations.25
nificant slopes, suggesting that reductions in serum urate
concentration were associated with worse pain and patient- Hypercholesterolemia Surrogate Marker:
reported outcomes across several scales.23 Low-Density Lipoprotein Cholesterol
Of 3463 records screened, 11 meta-analyses reported incon-
HIV Surrogate Marker: Plasma HIV RNA sistent evidence on the strength of association between
Of 506 records screened, 2 meta-analyses offered inconsis- reduction in low-density lipoprotein cholesterol and various
tent evidence on the strength of association between HIV-1 clinical outcomes (eTable 8 and eFigure 24 in Supplement 1).
RNA viral load and progression to AIDS or death (eTable 7 Although all meta-analyses claimed that reductions in low-
and eFigure 23 in Supplement 1). One reported that in- density lipoprotein cholesterol were associated with statisti-
creased levels of HIV-1 RNA were associated with higher cally significant improvements in at least 1 clinical outcome,
rates of progression to AIDS,24 whereas another reported 1 only 1 meta-analysis reported high-strength coefficients of
high-strength coefficient of determination between viral determination between low-density lipoprotein cholesterol

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 Research Original Investigation
Figure 3. Strength of the Associations Between 109 Surrogate Marker–
Clinical Outcome Pairs
40
No. of associations between surrogate
marker–clinical outcome pairs
30
20
10
0
Strong Moderate Modest Weak Limited
evidence evidence evidence evidence evidence
Strength of association between
surrogate marker–clinical outcome pairs
Strong evidence: correlation coefficients or coefficients of determination values
reported for all associations examined, and all associations classified as
statistically significant and high strength according to criteria proposed by the
Institute for Quality and Efficiency in Health Care (r ⱖ 0.85 or R2 ⱖ 0.72).14
Moderate evidence: r or R2 values reported for all associations examined, and 1
or more (but not all) classified as statistically significant and high strength.
Modest evidence: r or R2 values reported for some associations examined, and 1
or more (but not all) classified as statistically significant and high strength. Any
other r, R2, slopes, effect estimates, or results from meta-regression analyses
classified as statistically significant. Weak evidence: no r or R2 values classified
as both statistically significant and high strength, but all r, R2, slopes, effect
estimates, or results from meta-regression analyses classified as statistically
significant. Limited evidence: no r or R2 values classified as both statistically
significant and high strength; some r, R2, slopes, effect estimates, or results
from meta-regression analyses classified as statistically significant and some
not. No evidence: no r or R2 values classified as statistically significant and high
strength, and all r, R2, slopes, effect estimates, or results from meta-regression
analyses classified as nonstatistically significant.
and major vascular events (R2 = 0.85), major coronary events
(R2 = 0.85), and vascular mortality (R2 = 0.75 [n = 25 RCTs])
among trials investigating statin therapy.26
Hyperphosphatemia Surrogate Marker: Serum Phosphorus
Of 556 records screened, 1 meta-analysis reported low-
strength correlations between changes in serum phosphorus
level and improvements in all-cause mortality (r = 0.23; 95%
credible interval, −0.48 to 0.69 [n = 12 RCTs]) or cardiovascu-
lar mortality (r = 0.54; 95% credible interval, −0.98 to 1.0
[n = 4 RCTs]) (eTable 9 and eFigure 25 in Supplement 1).27
Hypertension Surrogate Marker:
Diastolic and Systolic Blood Pressure
Of 5541 records screened, 10 meta-analyses offered inconsis-
tent evidence on the strength of association between reduc-
tions in systolic or diastolic blood pressure and improve-
ments in cardiovascular outcomes and all-cause mortality
(eTable 10 and eFigure 26 in Supplement 1). The most recent
meta-analysis reported that reductions of 5 mm Hg in sys-
tolic blood pressure were associated with decreased inci-
dence of major adverse cardiovascular events (hazard ra-
tio = 0.89 [95% CI, 0.86-0.92] and hazard ratio = 0.91 [95% CI,
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Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments
0.89-0.94] among participants with and without cardiovas-
cular disease, respectively [n = 48 RCTs]).28
Hypertriglyceridemia Surrogate Marker:
Serum Triglyceride
Of 1869 records screened, 3 meta-analyses offered inconsis-
tent evidence on the strength of association between serum
triglyceride level and several clinical outcomes (eTable 11
and eFigure 27 in Supplement 1). One reported that each
increase of 10 mg/dL in absolute triglyceride level was asso-
ciated with a nonstatistically significant lower risk of vascu-
lar events (log relative risk, 0.4; 95% CI, −3.8 to 4.8 [n = 64
RCTs]),29 whereas another reported that changes in triglyc-
eride levels were predictive of cardiovascular events (log
No rate ratio slope, 0.488; P = .005 [n = 40 RCTs]) but the ob-
evidence
served slope was no longer statistically significant when
limited to RCTs of primary prevention (slope, 0.373; P = .11
[n = 25 RCTs]).30 A third meta-analysis reported that each
reduction of 1 mmol/L (88.5 mg/dL) in triglyceride level was
associated with a lower risk of major vascular events (rela-
tive risk, 0.84; 95% CI, 0.75-0.94 [n = 44 RCTs]).31
Osteoporosis Surrogate Marker: Bone Mineral Density
Of 1356 records screened, 6 meta-analyses offered inconsis-
tent evidence on the strength of association between
increases in bone mineral density (ie, hip, femoral neck, and
spine bone mineral density) and reductions in the risk of
several fracture types (ie, hip, vertebral, nonvertebral, and
spine fracture) (eTable 12 and eFigure 28 in Supplement 1).
The 2 most recent meta-analyses reported 18 coefficients of
determination, of which 3 were considered high strength
(hip bone mineral density and vertebral fractures, R2 = 0.73
[95% CI, 0.41-0.83], P < .001 [n = 14 RCTs]; femoral neck
bone mineral density and nonvertebral fractures, R2 = 0.65
[95% CI, 0.33-0.77], P < .001 [n = 17 RCTs]; and spine bone
mineral density and vertebral fractures, R2 = 0.63 [95% CI
0.41-0.73], P< .001 [n = 30 RCTs]).32,33
Pulmonary Fibrosis Surrogate Marker: Forced Vital Capacity
Of 85 records screened, 1 evaluated the strength of associa-
tion between forced vital capacity and the end points of mor-
tality (hazard ratio, 1.20; 95% CI, 1.12-1.28 per 2.5% relative de-
cline in forced vital capacity during 3 months) and disease
progression (hazard ratio, 1.46; 95% CI, 1.36-1.57 per 2.5% rela-
tive decline in forced vital capacity during 3 months [n = 6
RCTs]) among treated individuals (eTable 13 and eFigure 29 in
Supplement 1).34
Secondary Hyperparathyroidism Surrogate Marker:
Serum Parathyroid Hormone
Of 53 records screened, 1 offered low-strength evidence on the
strength of association between serum parathyroid hormone
level and all-cause mortality (r = 0.12; 95% credible interval,
−0.61 to 0.73 [n = 12 RCTs]) and cardiovascular mortality
(r = −0.03; 95% credible interval, −0.91 to 0.91 [n = 6 RCTs])
and continuous serum parathyroid hormone level and all-
cause mortality (r = −0.69; 95% credible interval, −0.88 to
−0.18 [n = 17 RCTs]) and cardiovascular mortality (r = −0.28;
jama.com
 Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments
95% credible interval, −0.98 to 0.96 [n = 5 RCTs]) (eTable 14
and eFigure 30 in Supplement 1).27
Type 2 Diabetes Mellitus Surrogate Marker: Hemoglobin A1c
Of 1766 records screened, 9 meta-analyses offered inconsis-
tent evidence on the strength of association between reduc-
tion in hemoglobin A1c level and improvements in all-cause
mortality, myocardial infarction, stroke, heart failure, kidney
injury, cardiovascular death, hospitalization for heart failure,
coronary heart disease, treatment-related discontinuations,
neuropathy, and peripheral vascular events (eTable 15 and eFig-
ure 31 in Supplement 1). One offered high-strength evidence
for the outcome of fatal stroke (R2 = 1.00 [n = 18 RCTs]),35
whereas 2 offered high-strength evidence for the outcome of
major adverse cardiovascular events.35,36
Discussion
This systematic review of the evidence examining surrogate
markers listed in FDA’s Adult Surrogate Endpoint Table that
may be used as clinical trial end points to support FDA ap-
proval of drugs treating nononcologic chronic diseases found
that more than half had no published meta-analysis examin-
ing the strength of their association with any clinical out-
come. Nearly 80% of these surrogate markers without a
published meta-analysis were classified by FDA as being ap-
propriate for traditional approval, including FEV1 for asthma
and serum creatinine for chronic kidney disease. For surro-
gate markers for which at least 1 eligible meta-analysis of clini-
cal trials was identified, most lacked high-strength evidence
of treatment effect associations with any clinical outcome.
Only 3 surrogate markers, FEV1 for chronic obstructive pul-
monary disease for the outcome of time to first occurrence of
a moderate to severe exacerbation, hemoglobin A1c for type 2
diabetes mellitus for the outcome of fatal stroke, and protein-
uria for primary glomerular disease treatment, were found to
have consistent evidence from published meta-analyses dem-
onstrating a high-strength treatment effect association with
a clinical outcome.
There is a lack of consensus on the minimum strength of
association between the treatment effects measured using
surrogate markers and those measured using target clinical
outcomes necessary to establish surrogacy. Although correla-
tion coefficients and coefficients of determination from
meta-analyses of clinical trials are often used to evaluate the
strength of association between surrogate markers and clini-
cal outcomes,8,9,14 these values are purely statistical, rely on
arbitrary cutoffs, and fail to capture information about the
study design, target outcome, and generalizability of the evi-
dence. Although more comprehensive methods to establish
surrogacy have been proposed (eg, the Biomarker-Surrogacy
Evaluation Schema),13,37 enhanced clinical trial reporting4,38
and greater availability of shared individual patient-level
data will facilitate more precise analyses and estimates.
To further enhance transparency, FDA’s Adult Surrogate
Endpoint Table could explicitly report the target outcomes
intended to be predicted by each surrogate marker for each
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© 2024 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Narayan Rao V Tummala on 04/23/2024
Original Investigation Research
disease. The FDA has maintained that the use of surrogate
markers in traditional approval requires, at minimum, evi-
dence from meta-analyses of clinical trials.11 The agency
could publicly report and routinely update an accompany-
ing summary of evidence supporting marker surrogacy for
clinical benefit, or clarify when no studies are available.
Although individual studies may be the only source of evi-
dence for surrogate markers classified by FDA as being
appropriate for accelerated approval, FDA could reconsider
whether to allow surrogate markers with low-strength evi-
dence from multiple meta-analyses to be used as primary
end points in clinical trials supporting traditional drug
approval. Additional studies explicitly designed to establish
surrogacy may be necessary for surrogate markers with no
or inconsistent evidence.39
Limitations
This study has several limitations. First, our findings may not
apply to surrogate markers used in clinical trials of drugs treat-
ing chronic diseases but not listed in FDA’s Adult Surrogate End-
point Table. Second, unpublished studies submitted to FDA
and other regulators may not have been identified. Third, by
our relying on the published literature indexed in MEDLINE,
some published studies indexed in other databases may not
have been identified. However, the search terms were broad
and MEDLINE (Ovid) indexes information from more than
5600 journals. Fourth, individual studies and meta-analyses
using observational cohorts were excluded because these stud-
ies are not considered robust sources of evidence for evaluat-
ing drug treatment effects or establishing surrogacy.40 Fifth,
identified meta-analyses could be susceptible to publication
bias because studies showing significant associations be-
tween surrogate markers and clinical outcomes may be more
likely to be published than those showing no association. Sixth,
exploratory subgroup analyses were not recorded, although
they could reveal variations for specific subgroups or settings
of use.
Conclusions
More than half of the surrogate markers listed in FDA’s Adult
Surrogate Endpoint Table that may be used as primary end
points in clinical trials supporting FDA approval of drugs
treating nononcologic chronic diseases were not found to
have a published meta-analysis evaluating associations
between treatment effects measured using surrogate markers
and clinical outcomes. For the surrogate markers for which at
least 1 meta-analysis was identified, most lacked high-
strength evidence of treatment effect associations with clini-
cal outcomes. These findings highlight the importance of
making publicly available a summary of the evidence sup-
porting surrogate end points that may be used to support
FDA approval of drugs treating chronic disease, which can
aid drug sponsors in choosing appropriate surrogate end
points for trials and guide physicians and their patients to
better interpret the clinical benefits of drugs approved
according to listed surrogate markers.
(Reprinted) JAMA Published online April 22, 2024 E7
 Research Original Investigation
ARTICLE INFORMATION
Accepted for Publication: March 4, 2024.
Published Online: April 22, 2024.
doi:10.1001/jama.2024.4175
Author Affiliations: Department of Epidemiology,
Rollins School of Public Health, Emory University,
Atlanta, Georgia (Wallach); Collaboration for
Regulatory Rigor, Integrity, and Transparency, Yale
School of Medicine, New Haven, Connecticut
(Wallach, Yoon, Doernberg, Mooghali,
Ramachandran, Ross); Department of Internal
Medicine, Massachusetts General Hospital, Harvard
Medical School, Boston (Yoon, Doernberg, Glick);
Center for Research on Health and Social Care
Management, SDA Bocconi School of Management,
Milan, Italy (Ciani); MRC/CSO Social and Public
Health Sciences Unit, School of Health & Wellbeing,
University of Glasgow, Glasgow, Scotland,
United Kingdom (Taylor); Robertson Centre for
Biostatistics, School of Health & Wellbeing,
University of Glasgow, Glasgow, Scotland,
United Kingdom (Taylor); Section of General
Internal Medicine, Department of Internal
Medicine, Yale School of Medicine, New Haven,
Connecticut (Mooghali, Ramachandran, Ross);
Yale National Clinicians Scholars Program, Yale
School of Medicine, New Haven, Connecticut
(Ramachandran, Ross); Department of Health
Policy and Management, Yale School of Public
Health, Yale–New Haven Health System,
New Haven, Connecticut (Ross); Center for
Outcomes Research and Evaluation,
Yale–New Haven Health System, New Haven,
Connecticut (Ross).
Author Contributions: Dr Wallach had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. Dr Wallach and Mr
Yoon served as co–first authors.
Concept and design: Wallach, Yoon, Ross.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Wallach, Yoon,
Doernberg.
Critical review of the manuscript for important
intellectual content: Wallach, Yoon, Glick, Ciani,
Taylor, Mooghali, Ramachandran, Ross.
Statistical analysis: Wallach, Yoon, Doernberg.
Obtained funding: Ross.
Administrative, technical, or material support:
Wallach, Yoon, Ramachandran.
Supervision: Wallach, Ross.
Methodological input on evidence grading and
quality assessment of surrogacy evaluation studies:
Ciani.
Conflict of Interest Disclosures: Dr Wallach
reported receiving grants from the Food and Drug
Administration (FDA) (through the Yale University–
Mayo Clinic Center of Excellence in Regulatory
Science and Innovation), National Institute on
Alcohol Abuse and Alcoholism (1K01AA028258),
and Johnson & Johnson (through the Yale
University Open Data Access Project); and
consulting fees from Hagens Berman Sobol Shapiro
LLP and Dugan Law Firm APLC outside the
submitted work. Dr Ramachandran reported
receiving grants from the Stavros Niarchos
Foundation and FDA; receiving consulting fees from
ReAct Action on Antibiotic Resistance strategy
policy program outside the submitted work; and
E8 JAMA Published online April 22, 2024 (Reprinted)
© 2024 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Narayan Rao V Tummala on 04/23/2024
Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments
serving in an unpaid capacity as chair of the FDA
task force for the nonprofit organization Doctors
for America and in an unpaid capacity as board
president for Universities Allied for Essential
Medicines North America. Dr Ross reported
receiving grants from FDA, Johnson & Johnson,
Medical Device Innovation Consortium, the Agency
for Healthcare Research and Quality, and National
Institutes of Health/National Heart, Lung, and
Blood Institute outside the submitted work; and
serving as an expert witness at the request of
relator's attorneys, the Greene Law Firm, in a qui
tam suit alleging violations of the False Claims Act
and Anti-Kickback Statute against Biogen that was
settled September 2022. No other disclosures
were reported.
Funding/Support: This work was supported by
grants from Arnold Ventures to the Yale
Collaboration for Regulatory Rigor, Integrity, and
Transparency.
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: Dr Ross is a Deputy Editor at JAMA but
was not involved in the decisions regarding this
article.
Additional Contributions: We thank Kate Nyhan,
MLS, a research and education librarian for public
health at Harvey Cushing/John Hay Whitney
Medical Library at Yale, for providing feedback on
our search strategy.
Data Sharing Statement: See Supplement 2.
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