the role of health-related quality of life data in the drug approval processes in the us and europe

The Role of Health-Related Quality of Life Data in theDrug Approval Processes in the US and EuropeA Review of Guidance Documents and Authorizations of Medicinal Products

from 2006 to 2010

Patrick Marquis,1 Martine Caron,2 Marie-Pierre Emery,2 Jane A. Scott,3 Benoit Arnould4 and Catherine Acquadro2

1 Mapi Values USA, Boston, Massachusetts, USA

2 Mapi Research Trust, Lyon, France

3 Mapi Values UK, Bollington, Cheshire, UK

4 Mapi Values France, Lyon, France

Abstract Objective: The objective of this research was to review the extent to which health-related quality of life

(HR-QOL) and other patient-reported outcomes (PROs) have played a role in drug approval and labelling

since 2006, when the US FDA issued its draft guidance on the use of PRO measures and the European

Medicines Agency (EMA), its reflection paper on HR-QOL.

Methods: This research was conducted through a systematic manual review of therapy area-specific regulatory

guidelines (US and EU) and product labels issued during the period 1 January 2006 to 16 November 2010.

Results: Fifteen (39.5% of all guidance documents) and 34 (35.8%) guidance documents containing

recommendations for the inclusion of PRO endpoints in clinical trials were released by the FDA and the

EMA, respectively. The FDA referred toHR-QOL (as a secondary endpoint) in 3 of the 15 (20%) guidances.

The EMA recommended use of HR-QOL endpoints in 22 of the 34 (65%) guidance documents. The FDA

approved 93 products with PRO endpoints in labelling (out of 432 total approvals). Of those, eight products

(8.6% of all products with a PRO claim) documented treatment benefits characterized as HR-QOL. The

EMA approved 54 products that included PRO endpoints in labelling (out of 248 total approvals), of which

16 products (29.6% of all products with a PRO claim) reflected HR-QOL data.

Conclusion:Our review shows that the patients’ perspective in clinical research is important for the EMAand

FDA, with HR-QOL endpoints still playing a minor role in product claims. Our analysis suggests that the

EMA’s receptivity to HR-QOL endpoints is greater than the FDA’s, and that both agencies value patient-

reported symptom data. Differences between the agencies’ acceptance of PRO endpoints, especially HR-

QOL, might reflect differences in their structure and organization. As the world’s largest medical regulatory

agency, the FDA employs an ‘army’ of experts to review submissions and develop guidance. This internal

expertise enables the FDA to take an active role in defining endpoints, developing guidance and regulations

that clarify their expectations, and enforcing regulatory policy. By contrast, the EMA, working with a

network of over 4500 European experts, relies on clinicians and the scientific community for the definition of

validity and the acceptance of an endpoint. Historically, the EMA has been more likely to accept existing

measures, including global assessment and diaries, provided the assessments are supported by peer-reviewed

publications of the development and validity of the instruments. Thus, the peer-review process and ac-

ceptance by the scientific and medical communities greatly influence the acceptance of PRO claims in EMA

product approvals. Finally, the FDA’s stance may be driven, in part, by the potential use of PRO in-

formation in direct-to-consumer advertising andwhether suchmeasures aremeaningful and interpretable by

patients. For the future, we believe that the empowerment of patients in healthcare decision making will

foster the use of specific PROs for evaluating the benefits of treatments on criteria that are meaningful to

patients, in addition to traditional clinical endpoints.

ORIGINAL RESEARCH ARTICLEPharm Med 2011; 25 (3): 147-1601178-2595/11/0003-0147/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Background

As patients are increasingly asked to pay for all or part of the

cost for their medicines, perspectives on the symptoms they

experience, how they feel and function, and their quality of life

(QOL) associated with their health condition and its treatment

have become important in the evaluation of the benefits and the

demonstration of the value of newmedicines. The patients’ per-

spectives were not considered in traditional clinical endpoints.

Today, patient-reported outcome (PRO) measures are used to

evaluate trial outcomes from the patients’ perspective (without

interpretation by investigators, physicians or anyone else).

PROs cover a range of concepts, from simple symptoms such as

pain to more complex multi-domain concepts such as health-

related quality of life (HR-QOL) or treatment satisfaction. These

can be captured in a variety of formats, such as event logs, rating

scales or checklists, using electronic or paper and pencil forms, as

well as responses recorded by telephone or in-person interviews.

PROs can be used asmeasures of effects ranging from symptoms

of a condition to a variety of impacts, someof themproximal and

some of them more distal.

Inclusion of HR-QOL and other PROs in the medicines

approval process has been evident at a disease-specific level to

varying degrees for a number of years. In the US, a review and

analysis of PRO endpoints as reported in clinical study de-

scriptions in approved product labelling of newmedical entities

(1997–2002) concluded that PROs had a significant role in the

development and evaluation of new drugs, but that more formal

guidance on the use of these measures was required from the US

FDA.[1] Several reviews of disease-specific guidelines from the

European Medicines Agency (EMA) during a similar period

(1995–2003) concluded that PRO assessments were welcomed,

but that more detailed guidance and a more systematic ap-

proach to the assessment and interpretation of HR-QOL was

required.[2-4] Differences in terminology and recommendations

were noted between the FDA and the EMA that highlighted a

need for closer collaboration between the two agencies.[2]

In 2006, new draft guidances were issued by both the FDAand

the EMA, describing the contribution that PROs can make to

support the case for the approval of a new medicine in the re-

spective regulatory environment. In theUS, guidance on the use of

PROs was issued in draft form in February 2006[5] and in its final

form in December 2009;[6] in Europe, the EMA reflection paper

on the use of HR-QOL in the evaluation of new products was

issued in July 2005 and became effective from January 2006.[7]

Fundamental to these guidance documents, and defined

specifically in the FDA guidance, PROs to be measured in any

given therapy area should be included within an ‘endpoint

model’, which defines in broad terms the hierarchy of endpoints

necessary to demonstrate treatment benefit.[6] The endpoint

model defines the primary endpoints required for the indication

and secondary endpoints for supportive concepts. Depending

on the condition, symptom improvement and other function

benefits reported by patients can be either primary or secondary

evidence of treatment benefit. For example, the endpoints used to

evaluate treatment benefit in primary insomnia (i.e. difficulty in

sleep initiation and maintenance, or lack of restorative sleep

associated with impairments of daytime functioning) range from

polysomnography to self-reported time to sleep onset, wake time

after sleeponset, total sleep time, daytime symptoms (e.g. tiredness,

sleepiness), daytime impact on activities and mood, and interac-

tionswith others. Symptoms and, less often, functional impacts are

used as primary endpoints in phase III studies. However, other

PRO endpoints, such as HR-QOL, may be included as secondary

endpoints andmaybe regarded as additional evidence of treatment

benefit that may be considered for inclusion in the labelling.

The relative importance of PROs as factors in the decision

to grant approval for a new product can be difficult to eval-

uate from publicly available documents. As labelling displays

‘‘the information the most useful to prescribers in treating

patients,’’[8] study endpoints (primary clinical or otherwise) are

not usually mentioned in the ‘indication’ section of the product

labelling,[5,9] except for treatment used for symptom relief. How-

ever, data from approved PRO endpoints may appear in the

‘clinical studies’ section of the Full Prescribing Information

(FPI) in US product details and in the ‘pharmacodynamic

properties’ section of the Summary of Product Characteristics

(SmPC) in Europe (section 5.1). These sections both describe

themain results of the clinical trials. In the FPI, they summarize

the evidence supporting effectiveness in subjects who were

studied, including statistically and clinically meaningful effects

on prospectively defined endpoints (but not whether the end-

point was identified as primary or secondary).[5] In the SmPC,

the section includes concise information relevant to prescribers

such as the main results (statistically compelling and clinically

relevant) regarding pre-specified endpoints or clinical outcomes.[9]

The objective of this research was to review the extent to

which HR-QOL and other PROs have played a role in medi-

cines approval and labelling since 2006, when the FDA issued

its draft guidance on the use of PRO measures and the EMA

issued its reflection paper on HR-QOL.

Methods

This study reviewed the role of HR-QOL outcomes and

other PROs in the US and European regulatory processes

148 Marquis et al.

ª 2011 Adis Data Information BV. All rights reserved. Pharm Med 2011; 25 (3)

through a systematic manual review of therapy area-specific

regulatory guidelines (US and EU) and product labels issued

during the period 1 January 2006 to 16 November 2010. In

Europe, we focused our analysis on the products approved and

guidelines issued by the EMA, which is responsible for the

scientific evaluation of medicines developed by pharmaceutical

companies for use in the EU through the centralized procedure.

We adopted the definition of PROs as stated in the final

FDAguidance: ‘‘A PRO is any report of the status of a patient’s

health condition that comes directly from the patient, without

interpretation of the patient’s response by a clinician or anyone

else,’’[6] and the definition of HR-QOL given by the EMA in its

reflection paper: ‘‘In the context of drug approval, HR-QOL is

considered to represent a specific type/subset of PROs, dis-

tinguished by its multi-dimensionality. Indeed, HR-QOL is a

broad concept which can be defined as the patient’s subjective

perception of the impact of his disease and its treatment(s) on

his daily life, physical, psychological and social functioning and

well-being.’’[7]

For this review, we excluded products for which evaluation

was based only on composite outcomes mixing physicians’

ratings, patients’ ratings and biological markers. Guidelines

relying only on observer ratings or composite endpoints (as

above) were excluded as well.

All documents were read individually by two independent

raters. Discrepancies were discussed until agreement was reached.

Regulatory Guidances

We researched clinical guidance documents released by both

agencies during the study period and identified those that in-

cluded recommendations for patient-reported assessments.

In the US, we analysed the FDA guidances from the Center

for Drug Evaluation and Research and the Center for Biologics

Evaluation and Research, but not from the Center for Devices

and Radiological Health. Guidance documents represent the

FDA’s current thinking on a particular subject and do not

create or confer any rights for or on any person and do not

operate to bind the FDA or the public.

In Europe, we analysed the EMA scientific guidelines, in

particular the clinical efficacy and safety guidelines. Only the

draft and adopted guidelines were reviewed (concept papers

and points to consider were not included). Guidelines are in-

tended to provide a basis for practical harmonization of the

manner in which the EUmember states and the EMA interpret

and apply the detailed requirements for the demonstration of

quality, safety and efficacy contained in the community direc-

tives. They also help to ensure that applications for marketing

authorization are prepared in a manner that will be recognized

as valid by the Agency.

Labelling Containing Patient-Reported Endpoints

The number and type of PROsmentioned in the labelling for

products approved during the study periodwere identified from

review of the PROLabels database. In addition, we compared

the FDA and EMA approvals for the same product: to docu-

ment patterns in the number and types of PROs included in

approved product labels and to determinewhether the nature of

the approvals reflects recent FDA and EMA guidances on as-

sessment of PRO and HR-QOL endpoints.

PROLabels (www.mapi-prolabels.org) is an online database

that tracks PROs included in FDA- and EMA-approved

medical product labels, in the FPI and the SmPC, respectively.

It covers PRO information available through regulatory agency

websites about PRO labelling claims (1995 to present for the

EMA; 1998 to present for the FDA). All original new drug ap-

plications (NDAs) and biologic labelling applications (BLAs)

approved by the FDA, as well as all supplemental NDAs and

BLAs, are reviewed as soon as they are published on the FDA

website. A similar process is followed for EMA approvals.

New or revised labels are reviewed to identify PRO data

reported in the description of treatment efficacy results. Infor-

mation is extracted from the label and from medical regulatory

reviews (if available) and the European Public Assessment

Reports (EPARs), including the SmPC and the scientific dis-

cussion (when available) to document the methods used to

develop the PRO endpoints, details regarding the instrument

used (e.g. domains, name, recall period, response scale), ther-

apeutic class of the medical product, mechanism of action,

therapeutic area (Medical Subject Headings [MeSH] classifica-

tion), and general (MeSH term) and specific (reported in label)

therapeutic indications. In addition, information about the

application is recorded, including regulatory agency, reference

number, marketing authorization holder/sponsor, date of drugapproval and date of revision of the label. Further information

about the review criteria and information collected in the

PROLabels database has been published elsewhere.[10-12]

Results

Regulatory Guidances

Between 1 January 2006 and 16 November 2010, 15 and

34 guidance documents were released by the FDA[13-27] and

the EMA,[28-61] respectively, containing recommendations for

Role of HR-QOL in the Drug Approval Process 149


the inclusion of one or more PRO endpoints in clinical trials.

Table I presents a summary of the data, and supplementary

table I (see the Supplemental Digital Content 1, http://links.

adisonline.com/PMZ/A3) lists the guidance documents iden-

tified. These guidance documents can be sourced in full from

the websites of the FDA[62] and EMA.[63] Additional web links

to the individual guidance documents and extracts providing

details of specific recommendations regarding PROorHR-QOL

instruments to be used are also included in the references.

These guidance documents reflect 39.5% of the total number

of clinical guidance documents published in draft or final form

by the FDAand 35.8% of the total draft and adopted guidelines

published by the EMA during that time.

Explicit reference to the HR-QOL reflection paper was

made in five EMA guidelines (14.7% of all guidelines; 22.7% of

the guidance documents referring to HR-QOL).[40,41,46,50,53]

Nine (60%) of the FDA guidelines referred to the guidance on

PRO measures.[13,17,18,20-23,26]

The clarity of the guidances regarding the way in which

PROs should be evaluated varied across therapy areas, ranging

from recommendations of specific validated instruments to

general acknowledgement that PROsmight be useful, but with-

out recommendation of a suitable measure to use (see supple-

mentary table I in the Supplemental Digital Content). Nine of the

15 FDA guidances and 26 of the 34 EMA guidances recom-

mended using a validated instrument, although a smaller number

specified a named validated instrument (3/15 FDA; 13/34 EMA).

The FDA referred to HR-QOL specifically (as a second-

ary endpoint) in 3 of the 15 (20%) guidances mentioning

PRO endpoints – for chronic obstructive pulmonary dis-

ease (COPD), oncology and weight management.[15,17,19]

The EMA recommended use of HR-QOL endpoints in

22 of the 34 (65%) guidances mentioning PRO assess-

ments.[28-31,33,35,37-41,44-46,48-50,52,54,56,58,60]

Indications and disease areas differ slightly between the

agencies (see figure 1). In only two cases did the guidelines refer

to the same indication: i.e. COPD and weight management.

Both agencies advise the use of HR-QOL as a secondary end-

point in the latter, but differ regarding the use of HR-QOL

endpoints in COPD (see the Comparison of Claims with Guid-

ance Documents section).

The FDA never recommends HR-QOL as a primary end-

point, whereas the EMA recognizes that it can be used as such

in three specific and restricted indications: in cystic fibrosis,[50]

COPD[58] and haematological malignancies.[56]

In cystic fibrosis, it is clearly stated that: ‘‘A claim of im-

provement in QoL (or lack of deterioration) would be accept-

able only in section 5.1 of the SmPC. Such a claim should Table

I.Patient-reportedoutcome(PRO)endpoints

recommendedin

US

FDA

orEuropeanMedicinesAgency(EMA)guidancedocuments

issuedbetween1January

2006and

16November2010

Year

No.ofFDAguidancedocuments

No.ofEMAguidancedocuments

HR-Q

OL

symptoms

otherPROsa

totaln

o.ofguidance

totaln

o.ofguidance

HR-Q

OL

symptoms

otherPROsa

totaln

o.ofguidance

totaln

o.ofguidance

PS

PS

PS

withPROs(%

all)

(draftandfinal)

PS

PS

PS

withPROs(%

all)

(draftandfinal)

2006

00

21

11

29

06

25

28

821

2007

03

32

03

59

03

26

05

421

2008

00

20

00

24

05

43

23

818

2009

00

21

00

25

15

32

25

615

2010

00

33

61

411

23

65

515

820

2006–10

03

12

77

515(39.5)

38

322

17

21

11

36

34(35.8)

95

a‘OtherPROs’m

ayincludemeasuresofpreference,satisfaction,functioningandotherconcepts

thatare

evaluable

bypatients.

HR-Q

OL=health-relatedqualityoflife;P=primary;S=seco

ndary.

150 Marquis et al.


be supported by studies specifically designed to demonstrate a

HRQL benefit, withHRQLassessment as primary endpoint.’’[50]

In haematological malignancies, HR-QOL is considered as a

co-primary endpoint in the case of a treatment administered

without curative intent where the prognosis is poor and where

only short-term disease control is expected (palliative therapy):

‘‘In a study conducted with BSC [best supportive care] as ref-

erence therapy, the objective should be to demonstrate pro-

longed OS [overall survival] and/or improved symptom control

or quality of life (QoL). The latter requires that the study is

conducted under proper double-blind conditions.’’[56]

As for COPD, HR-QOL is only envisaged as a co-primary

endpoint with lung function.[58]

In these three cases, HR-QOL is never envisaged as a sole

primary endpoint, and the claim will only be acceptable in

section 5.1 of the SmPC.

On the other hand, there are indications where the EMA

clearly specifies that HR-QOL measures are not fully estab-

lished (migraine[36]), or validated (insomnia[51]), or that the use

of HR-QOL as a primary efficacy variable in pivotal studies is

discouraged (Parkinson’s disease[42]).

Label Claims Containing Patient-Reported Outcome

Measures

During the study period, the FDA approved 93 products (of

432 total approvals) with label claims that included PRO end-

points (table II). Of those, eight products (8.6% of all products

with a PRO claim) documented treatment benefits character-

ized asHR-QOL. The vast majority of the PRO claims reflected

treatment benefit measured by patient-reported symptoms

(104 claims representing 79 products, corresponding to 85%of all products with a PRO claim approved during this period).

During the same period, the EMA approved 54 products

(of 248 total approvals) that included PRO endpoints, of which

16 products (29.6% of all products with a PRO claim) reflected

HR-QOLdata (table II). Like the FDA, the vast majority of the

PRO claims reflected treatment benefit measured by patient-

reported symptoms (i.e. 64 claims representing 48 products,

corresponding to almost 89% of all products with a PRO claim

approved during this period).

Thus, the inclusion of HR-QOL data in approved product

documents was >3 times more common in EMA than FDA ap-

provals, although both agencies reported PRO data in roughly

21.5% of labels for new products approved.

Since 2006, the number of products approved by the FDA

with an HR-QOL claim has steadily decreased. As for the

EMA, the number of products with HR-QOL cited in section

5.1 of the SmPC showed a rise in 2007 (12%) but has remained

stable since then (around 6%).

Figures 2 and 3 summarize PRO and HR-QOL claims by

broad therapeutic areas. In the US, HR-QOL claims were

dominated by respiratory conditions (four out of eight; how-

ever, PRO claims in general are more widely distributed across

therapeutic areas, as seen in figure 2).

In Europe, HR-QOL claims represent a broader range of

conditions and indications, dominated by sixHR-QOL claims for

anaemia treatments. In contrast, PRO claims in general are more

widely distributed across therapeutic areas, as seen in figure 3.

Comparison of the FDA- and the EMA-Approved Labels

Although each agency granted a number of claims that in-

cluded PROs, there were few products that had PRO claims

from both agencies. During the time period studied here, the

FDA and the EMA granted 12 compounds (24 products) ap-

proval for PRO content in the product label (see supplementary

table II in the Supplemental Digital Content).

Out of these 12 compounds, three present labelling claims

that differ according to the agency: fosaprepitant (Emend� or

Ivemend�) for chemotherapy-induced nausea and vomiting,

golimumab (Simponi�) for ankylosing spondylitis, and var-

enicline (Chantix� or Champix�) for smoking cessation.

The impact of nausea and vomiting on patients’ daily lives as

measured by the Functional Living Index – Emesis (FLIE) is

clearly indicated in the labelling claim of Emend� (FDA), while

there is no mention of such impact in the section 5.1. of the

9

EMAFDA

8

7

6

5

Num

ber

of g

uida

nces

4

3

2

1

0

Disease area

Respir

ator

y

Infe

ction

s

Neuro

logy

Men

tal

Mus

culos

kelet

al

Neopla

sms

Pain

Met

aboli

c

Gastro

intes

tinal

Derm

otolo

gical

Cardio

vasc

ular

Other

s

Fig. 1. Number of US FDA and European Medicines Agency (EMA) gui-

dance documents publishedbetween 1 January 2006 and 16November 2010

that contained recommendations for the inclusion of one or more patient

reported outcome endpoints in clinical trials, grouped by disease area.



Table II. Patient-reported outcomes (PROs) included in the Full Prescribing Information or Summary of Product Characteristics (SmPC) for products approved

by the US FDA or the European Medicines Agency (EMA) between 1 January 2006 and 16 November 2010

Parameter Year

2006 2007 2008 2009 2010 2006–10

FDA approvals (n)

HR-QOL primary 0 0 0 0 0 0

HR-QOL secondary 3 3 1 0 1 8

Signs and symptoms primary 14 12 15 15 11 67

Signs and symptoms secondary 9 9 10 9 0 37

Other PRO primary 1 1 2 1 4 9

Other PRO secondary 8 3 3 2 2 18

Products approved with a PRO in labela 21 16 20 21 15 93

Products approved with HR-QOL in labela 3 3 1 0 1 8

Products approved with signs and symptoms in labela 18 13 19 20 9 79

All product approvals 100 78 84 97 73 432

EMA approvals (n)

HR-QOL primary 0 0 0 0 0 0

HR-QOL secondary 0 8 3 6 1 18

Signs and symptoms primary 4 4 9 9 3 29

Signs and symptoms secondary 2 8 7 16 2 35

Other PRO primary 2 2 1 4 0 9

Other PRO secondary 2 7 4 14 0 27

No. of products approved with a PRO cited in SmPC 5.1.a 5 13 11 21 4 54

No. of products approved with HR-QOL cited in SmPC 5.1.a 0 8 3 4 1 16

No. of products approved with signs and symptoms cited in SmPC 5.1.a 5 10 10 20 3 48

All product approvals 42 66 50 68 22 248

Products with a PRO claim/all drug approvals (%)

FDA 21.0 20.5 23.8 22.7 20.6 21.5

EMA 11.9 19.7 22.0 30.9 18.2 21.7

Products with a symptom claim/all drug approvals (%)

FDA 18.0 16.7 22.6 20.6 12.3 18.3

EMA 11.9 15.2 20.0 29.4 13.6 19.4

Products with a symptom claim/all products with a PRO claim (%)

FDA 85.7 81.3 95.0 95.2 60.0 85.0

EMA 100.0 76.9 90.9 95.2 75.0 88.9

Products with an HR-QOL claim/all drug approvals (%)

FDA 3.0 3.9 1.2 0.0 1.4 1.9

EMA 0.0 12.1 6.0 5.9 4.6 6.5

Products with an HR-QOL claim/all products with a PRO claim (%)

FDA 14.3 18.8 5.0 0.0 6.7 8.6

EMA 0.0 61.5 27.3 19.1 25.0 29.6

a All indications included. One product with several indications is counted once and PROs are counted for all indications, explaining why the number of PROs

exceeds the number of products.

HR-QOL= health-related quality of life.

152 Marquis et al.


SmPC of Ivemend� (EMA), although the FLIE was adminis-

tered to patients in the studies submitted to the EMA.

Results of this evaluation are fully described in the scientific

discussion of the EPARdated 5 February 2008 and its variation

published on 24 September 2010.[64,65]

In the scientific discussion of 2008, the assessment is clearly

in favour of Ivemend�: the results of the combined analysis

of studies P052 and P054 show that a higher proportion of

patients receiving the aprepitant regimen reported minimal or

no impact of nausea and vomiting on daily life (74.4% vs

63.9% – table V of the report[64,65]). In the Ivemend� – H-743-

X-06 :EPAR – Assessment Report – Variation it is clearly

stated that ‘‘Also with respect to this outcome measure, it ap-

pears reasonable to conclude that overall non-inferiority has

been shown, even though trends towards worse results in the

vomiting specific domain have been noted.’’[64,65] These out-

comes are quite similar to those reported in the studies sub-

mitted to the FDA. Unfortunately, no reasons are given for the

omissions in the EMA SmPC.

Simponi� is another example of differences between the

EMA and the FDA. The EMA SmPC for the indication of

ankylosing spondylitis describes assessments of physical func-

tion and HR-QOL. Those PROs are not even considered in the

studies submitted to the FDA. It is interesting to note that the

EMA SmPC stipulates that HR-QOL is measured by the physi-

cal component of the Short Form 36 (SF-36) Health Survey

Questionnaire. This seems to be in contradiction with the

statement of the EMA reflection paper on the use of HR-QOL,

which indicates: ‘‘y the notion of multidimensionality is a key

component of definition of HR-QOL. A single domain, e.g.

physical functioning or fatigue, is not considered as a HR-QOL

(i.e. it cannot be the basis for a claim for a global HR-QOL

improvement), even though it is a patient-reported.’’[7]

It could be argued that the physical component of the SF-36

is determined by four dimensions. However, these four dimen-

sions only cover physical aspects of health.

As for the FDA Chantix� labelling, the major difference

with the EMA lies in the use of a patient’s self-report tomeasure

abstinence from smoking as a primary endpoint verified by mea-

surement of exhaled carbonmonoxide (CO <10 parts per million)

at weekly visits. In addition, unlike the EMA, craving is not

indicated in the FDA label, although it is assessed as a sec-

ondary endpoint by the same PRO instrument (i.e. the Brief

Questionnaire of Smoking Urges [QSU-Brief]). Reasons for

this decision are found in the FDA Medical Review: ‘‘Var-

enicline’s effects on ) craving * and ) urge to smoke * both

appear to bemeasuring the same construct, probably described,

per Dr. Scott, as ‘‘urge to smoke.’’ However, a consistent effect

on the instruments and questions measuring this concept ap-

pears to be demonstrated.’’

Comparison of Claims with Guidance Documents

Comparing claims with guidance documents, our analysis of

the PRO claims issued shows that for the FDA, not a single

HR-QOL claim was in a condition having an HR-QOL re-

commendation in the guidelines issued between 1 January 2006

and 16 November 2010 (table III). Thus, we could not see a

pattern between HR-QOL recommendations in guidances and

actual label content reflecting these concepts. For the EMA, we

found four conditions in which there was a match between the

products approved and the guidances issued: psoriatic arthritis,

ankylosing spondylitis, insomnia and multiple sclerosis, cor-

responding to three different products: Circadin�, Extavia�

and Simponi� (table III). One product (Circadin�) was ap-

proved before the publication of the corresponding guidance.

The analysis of the SmPC revealed that chosen endpoints were

similar to those advised in the insomnia guidance; this is con-

sistent with the guidance as a description of current practices.

Extavia� and Simponi� (for the psoriatic arthritis indication)

25

PRO claimsHR-QOL claims

20

15

10

Num

ber

of p

rodu

cts

5

0

Therapeutic areaBeh

aviou

r and

beh

aviou

r mec

hanis

ms

Cardio

vasc

ular d

iseas

e

Derm

atolo

gy

Disord

ers o

f env

ironm

enta

l orig

in

Gastro

ente

rolog

y

Genet

ic dis

ease

Gynae

colog

y

Haem

ic dis

ease

Neuro

logy

Oncolo

gy

Ophth

almolo

gy Pain

Men

tal d

isord

ers

Respir

ator

y

Rheum

atolo

gy

Urolog

y

Fig. 2. Summary of US FDA patient-reported outcome (PRO) and health-

related quality of life (HR-QOL) claims in product labelling for agents ap-

proved between 1 January 2006 and 16 November 2010, grouped by broad

therapeutic areas.



were approved after the publication of their corresponding

guidance, and the endpoints chosen are in line with those re-

commended in their respective guidance documents. As for

ankylosing spondylitis, the almost simultaneous dates of guid-

ance publication and product approval (Simponi�), plus the

concordance of endpoints, suggest the recognition of existing

practices within the guidance.

Overall concordance would not be expected yet, since trials

take years to complete and the earliest guidance we reviewed

was dated 2006. Trials that specifically considered each guid-

ance may still be continuing and the data not yet available.

Discussion

Our review of guidance documents and products with an

approved PRO label indicates that representing the patient’s

perspective in clinical research is important for both the EMA

and the FDA. However, HR-QOL endpoints play a minor role

in the approval of drugs. Although the percentage of products

with an HR-QOLmention in the label is >3 times higher for the

EMA (29.6%) than for the FDA (8.6%) among all products

with a PRO label, when compared with all drug approvals, the

percentages are quite low (FDA 1.9%, EMA 6.4%). Among

guidances that included any PRO, the FDA recognized the

relevance of HR-QOL endpoints in only 20%. In contrast, the

EMA acknowledged the importance of HR-QOL endpoints in

65% of guidances that included any PRO endpoints. Those

findings suggest that receptivity to HR-QOL concepts is higher

in the EMA,while the FDA seems to prefer symptom-based data.

There may be several reasons for the differences observed

between the percentage of the FDA and EMA guidelines re-

commending HR-QOL endpoints and the number of labels

including HR-QOL for the corresponding therapeutic area:

(i) the reluctance of regulators, particularly in the US, to allow

labels including HR-QOL wording; (ii) the lack of documenta-

tion and sometimes quality of the HR-QOL data, including the

non-compliance with current standards for evaluating PROs in

clinical trials; and (iii) the decision of sponsors to limit the end-

points to critical ones to get the product approved.

Willke et al.[1] reviewed and analysed PRO endpoints as re-

ported in clinical study descriptions in product labelling of new

molecular entities approved in the US from 1997 through 2002.

They found that PRO endpoints appear in 30% of all labels

(64 products) and that 22 of the 23 drugs approved only on

PRO endpoints were approved on direct patient symptom re-

ports. The latter is in concordance with our finding about FDA

preference for symptom-based data. The percentage decrease in

the use of PRO endpoints (in our review, PRO endpoints re-

present 21.5% of all FDA approvals) might be explained by the

approval of products belonging to different therapeutic classes

in Willke’s review (e.g. anti-inflammatory, urological, oph-

thalmical, gastrointestinal or allergic).

It is interesting to note that Gondek et al.[66] came to a

similar conclusion about EMA receptivity toHR-QOL, although

their study was focused mainly on oncology. In another study in

oncology (a review of PRO supporting FDAanticancer approval

from 1995 to the end of 2006), Rock et al.[67] showed that nine

treatment indications have been approved for seven anticancer

products based either on symptom palliation or improvement in

a functional endpoint. These approvals represented only 10% of

all treatment indications approved.HR-QOLwas used only once

(gemcitabine for non-small cell lung cancer).

In the research conducted by Szende et al.,[4] all published

EMA guidance documents and regulatory information for

products authorized at the EMA and appearing in the EPAR

database between 1995 and 2003were examined for reference to

HR-QOL and other PROs. They found that 53% of the guid-

ances retrieved included recommendations on PROs. However,

they included ‘concept’ papers and ‘points to consider’ in their

review, which we did not. When those are deleted, the percen-

tage rises to 58% (21 out of a total of 36). Our review identified

34 guidelines out of a total of 95 (35.8%). When we examined

the list of guidelines already including PROs and compared it

with the indications retrieved in our review, we discovered six

matches: HIV infection, migraine, multiple sclerosis, Parkinson’s

disease, stable angina pectoris, and weight control. Interestingly,

at that time, ankylosing spondylitis was not seen as a potential

PRO claimsHR-QOL claims

9876

Num

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5432

Behav

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ehav

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echa

nism

s

Cardio

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iseas

e

Conge

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and

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y dise

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atolo

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Gastro

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Haem

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Men

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and

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Ophth

almolo

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Respir

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y

Rheum

atolo

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Urolog

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Viral d

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10

Therapeutic area

Fig. 3. Summary of European Medicines Agency patient-reported outcome

(PRO) and health-related quality of life (HR-QOL) claims in product labelling

for agents approved between 1 January 2006 and 16 November 2010,

grouped by broad therapeutic areas.

154 Marquis et al.


candidate for PRO recommendation (2003 concept paper). Fif-

teen of the 21 draft and adopted guidelines retrieved included an

HR-QOL recommendation (71.4%). Our review found that up

to 65% of the guidances included any PRO endpoints. All these

difference might be explained by different disease areas covered

by the 1995–2003 guidelines (only six matches were found to

those covered in our review).

As for the product-level information, Szende et al.[4] identified

81 products (34% of those submitted) that included HR-QOL or

other PRO information.Most of themwere antineoplastic agents

(32%).[4] In our review, we identified 54 products with PRO in-

formation representing 21.8% of all drug approvals. Most of

them had an indication in respiratory, neurological, haemic and

rheumatological diseases. In the Szende et al. review, HR-QOL

information was included in 55 products (66.9%).[4] Our review

identified 16 products, representing 29.6% of all products with a

PRO claim. Again, the difference might be explained by the dif-

ferences in therapeutic classes of approved products.

Papanicolaou et al.[3] reviewed the European guidelines on

how HR-QOL research should be conducted in clinical trials.

Published product-level information through EPARs of all

approved drugs was also reviewed to investigate the actual role

of HR-QOL data in the European regulatory process. From

1995 to 23 March 2003 they identified 20 of 50 guidances

including reference to, or recommendations for, HR-QOL.

When we deleted all ‘points to consider’, we found reference to

13 draft or adopted guidelines (15 in the Szende et al. review[4]),

with two draft guidelines not included: panic disorder and

psoriasis. The main difference from the Szende et al. review is a

severe criticism of the terminology used: ‘‘In general, most of

Table III. The US FDA- and European Medicines Agency (EMA)-approved products including a health-related quality of life mention in their label and

corresponding guidance (1 January 2006 to 16 November 2010)

Agency Product

(brand name)

Indication Therapeutic area Date of

approval

Guidance published between 01/01/2006and 16/11/2010 (Yes/No – date)

FDA Coreg CR Mild to moderate heart failure Cardiovascular disease 20/10/2006 No

FDA Soliris Haemoglobinuria, paroxysmal Haemic disease 16/03/2007 No

FDA Casodex Prostatic neoplasms Oncology 19/12/2008 No

FDA Seroquel XR Bipolar disorder Psychiatry 17/05/2007 No

FDA Advair HFA Asthma Respiratory 08/06/2006 No

FDA Symbicort Asthma Respiratory 21/07/2006 No

FDA Veramyst Rhinitis, allergic, perennial Respiratory 27/04/2007 No

FDA Dulera Asthma Respiratory 22/06/2010 No

EMA Stelara Psoriasis Dermatology 16/01/2009 No

EMA Resolor Constipation Gastroenterology 15/10/2009 No

EMA Soliris Haemoglobinuria, paroxysmal Haemic disease 20/06/2007 No

EMA Binocrit Anaemia Haemic disease 28/08/2007 No

EMA Epoetin alfa Hexal Anaemia Haemic disease 28/08/2007 No

EMA Abseamed Anaemia Haemic disease 28/08/2007 No

EMA Silapo Anaemia Haemic disease 18/12/2007 No

EMA Retacrit Anaemia Haemic disease 18/12/2007 No

EMA Circadin Insomnia Neurology 29/06/2007 Yes – 22 Oct 2009 – draft

EMA Extavia Multiple sclerosis Neurology 20/05/2008 Yes – 16 Nov 2006 – adopted

EMA Yondelis Ovarian neoplasms Oncology 17/09/2007 No

EMA Iressa Carcinoma, non-small cell lung Oncology 24/06/2009 No

EMA Votrient Carcinoma, renal cell Oncology 14/06/2010 No

EMA Avamys Rhinitis, allergic, perennial and seasonal Respiratory 11/01/2008 No

EMA Alisade Rhinitis, allergic, perennial and seasonal Respiratory 06/10/2008 No

EMA Simponi Arthritis, rheumatoid Rheumatology 01/10/2009 No

EMA Simponi Arthritis, psoriatic Rheumatology 01/10/2009 Yes – 14 Dec 2006 – adopted

EMA Simponi Spondylitis, ankylosing Rheumatology 01/10/2009 Yes – 23 Apr 2009 – adopted



the recommendations that referred to the measurement of HR-

QOL were generic and vague, using nonstandard terminology

that was also inconsistent across the documents.’’

Based on our review, our judgement is less severe, and we

believe that the publication of the HR-QOL reflection paper as

well as training on HR-QOL issues among experts involved in

the design of the EMA guidance had an impact on the clarity of

the guidance documents issued between 2006 and 2010. The

guidelines about osteoarthritis, irritable bowel syndrome,

COPD and Crohn’s disease, which were only points to consider

in 2003, were considerably revised and clarified when their

status changed to draft or adopted. On the other hand, new

guidelines in gastroesophageal reflux disease, premenstrual

dysphoric disorder and ankylosing spondylitis are very de-

tailed, clear and precise.

Differences between the EMA’s and FDA’s appreciation

and preference of PRO endpoints, especially HR-QOL, might

be explained by their differences in structure and organization.

As the world’s largest medical regulatory agency, the FDA

employs an ‘army’ of medical and methodological experts to

review submissions and develop guidance. This internal ex-

pertise enables the FDA to take a very active role in defining

endpoints that are needed to evaluate treatment effects, devel-

oping guidance and regulations that clarify the FDA expecta-

tions, and enforcing regulatory policy. The statutes that the

FDA enforces require that product claims be supported with

well defined and reliable clinical trial endpoints. The FDA’s

most recent position is that PRO endpoints must be informed

by an understanding of the condition that is grounded in

systematic qualitative research with patients who have the

condition that will be studied in the trial. This helps ensure that

PRO assessments used to measure endpoints provide accurate

data because they are easy to understand and relevant to the

patients asked to complete them. Using their internal expertise

in measurement and clinical matters, the FDA conducts de-

tailed reviews of existing and newly developed PROs to ensure

they have content validity and that claims based on the end-

points are neither false nor misleading. Finally, as part of its

Critical Path Initiative, the FDA has recently released a draft

guidance on the Qualification Process for Drug Development

Tools (DDTs).[68] The guidance provides a framework for how

drug developers and manufacturers may submit and seek

qualification approval for tools thatmay have only been used in

one instance, but could potentially serve as platforms for ac-

celerating development activities. Biomarkers and PRO instru-

ments are the main tools considered in this guidance. Knowing

that a certain PRO is qualified in advance with the FDA as a

DDT can accelerate trial and approval work.

By contrast, the EMA, working with a network of over

4500 European experts, relies on clinicians and the scientific

community for the definition of validity and the acceptance of

an endpoint. In addition, experts involved in the development

of guidelines or review of approval submissions are often clin-

icians still active in their countries with, for some of them, daily

contact with patients. Historically, the EMA has been more

likely to accept existing measures, including global assessment

and diaries, provided that the assessments are supported by peer-

reviewed publications of the development and validity of the in-

struments. Thus, the peer-review process and the acceptance by

the scientific and medical communities greatly influence the like-

lihood of PRO claims in the EMA product approvals.

The FDA’s apparently greater interest and detailed review of

PRO endpoints in clinical trials and product labels may be

driven, in part, by the potential use of such information in

direct-to-consumer advertising. Clearly, direct-to-consumer

messages based on PRO data can be very compelling to the

healthcare consumer, offering a promise of treatment benefits

in terms that mean the most to patients themselves: i.e. how

they feel and what they are able to do. Anticipating such pro-

motion based on the content of the package insert or drug

labelling, the FDA undertakes an extreme level of care in de-

termining whether and which PROs may serve as clinical trial

endpoints that are meaningful and interpretable by patients.

What of the representation of HR-QOL claims in propor-

tion to other patient reports, such as symptom assessments?We

believe that two forces are at work here, particularly in the US.

First, the FDA has set a very high hurdle with its definition of

HR-QOL and requirements for proving an improvement –

acknowledging the concept is multidimensional and potentially

abstract. It is these qualities that may make the HR-QOL claim

of limited usefulness in communicating treatment benefit.

Second, clinicians recommend interventions to improve specific

signs or symptoms of a condition.

Bottomley et al.,[69] in their review of the FDA PRO guide-

line and the EMA HR-QOL reflection paper, considered that

these documents were ‘‘important steps towards the accepta-

tion and appreciation of patient viewpoint, and the creation of

significant evidence in the drug approval process.’’ However,

they deplored the stringency of the FDA for well established

PRO or HR-QOL measures (e.g. the European Organisation

for the Research and Treatment of Cancer Quality of Life

Questionnaire [EORTC QLQ] C30) with a long history of ef-

fective use and significant evidence of real-world validity.

There are several limitations to our study. First, it takes time

to see the effect of guidance in the results of clinical trials and

thus claims, for the simple reason that it takes years to run a

156 Marquis et al.


trial. Therefore, effects of the 2006–10 published guidances are

not fully seen. Second, the differences cited between the EMA

and the FDA may simply be because of differences between

drugs that were approved during the limited time period of the

study andmay not reflect any tendency for the EMA to approve

more HR-QOL endpoints.

As for the relatively low percentage of products with PRO

claims (around 21.5% for both agencies), it is difficult to draw

conclusions. We cannot determine whether this percentage is

just right or too low. We may wonder whether PRO evaluation

for all the drugs without PRO claims (78.5%) was judged not

relevant or not even considered. However, we agree with

Doward et al.[70] who, in a recent paper, aptly pointed out that

PROs should be considered beyond the label claim and ad-

vocated regulators to consider patients’ views with more dedi-

cated attention: ‘‘The FDA may be unwilling to consider PRO

data beyond first order impacts (signs and symptoms). How-

ever, it is clear when talking to patients and patient groups that

such concerns are often ofminor concern to their determination

of the impact of disease and the effectiveness of treatments.

Patients have very real ideas about what states of physical and

emotional well-being (and ultimately QoL) are acceptable and

may not always agree with clinicians and regulators on whether

treatments are beneficial.’’ Doward et al. also recognized the

importance of health payers and agencies involved in re-

imbursement and pricing decisions, who should be considered

as key players in the future.[70] They may have an influence in

the extension of PRO evaluation to new therapeutic areas or in

the identification of broader PRO outcomes.

Conclusions

Our study shows that representing the patients’ perspective

in clinical research is important for both the EMA and the

FDA, with broad HR-QOL endpoints playing a minor role in

product claims. Our analysis suggests that the receptivity of the

EMA to HR-QOL endpoints is greater than the FDA’s, and

that both agencies value patient-reported symptom data. Our

results are comparable to previous analyses within an acceptable

margin, with the main differences observed due to products

approved in different therapeutic classes or guidances published

in different therapeutic areas. We showed that the generic gui-

dances published on PRO measures (FDA) and HR-QOL

(EMA) are acknowledged in disease-specific guidelines, and that

guidelines issued by the EMAduring our period of analysis have

gained in precision and clarity compared with previous periods.

As for the future of PRO evaluation, we believe that the shift

toward patient-centric healthcare and the empowerment of

patients in healthcare decision-making through an increase in

access to information and active advocacy groups will foster the

development of specific PRO endpoints relevant to them for

evaluating treatment benefits, in addition to traditional clinical

endpoints.

Acknowledgements

This study was not funded by any agencies external to Mapi Values

USA, LLC or Mapi Research Trust. Mapi Values and Mapi Research

Trust have developed the PROLabels database. Mapi Research Trust

maintains and sells access to the PROLabels database, which is used in this

work to facilitate our review of the data on PRO claims. The authors have

no conflicts of interest that are directly relevant to this study.

The authors gratefully acknowledge the support of Laure-Lou Perrier,

Virginie Vaissier and Mylene Castex, Project Managers at Mapi Research

Trust, for their assistance in data collection and analysis.

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Street, Boston, MA 02114, USA.

E-mail: [email protected]

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