Health Policy

Advancing patient-centric care: integrating patient reported

outcomes for tolerability assessment in early phase clinical
trials – insights from an expert virtual roundtable
Christina Yap,a,∗ Olalekan Lee Aiyegbusi,b,ab,ac,ad,ae Emily Alger,a Ethan Basch,c,af Jill Bell,d Vishal Bhatnagar,e David Cella,f Philip Collis,b
Amylou C. Dueck,g Alexandra Gilbert,h Ari Gnanasakthy,i Alastair Greystoke,j Aaron R. Hansen,k,ag Paul Kamudoni,l Olga Kholmanskikh,m
Bellinda L. King-Kallimanis,n Harlan Krumholz,o Anna Minchom,p Daniel O’Connor,q Joan Petrie,r Claire Piccinin,s Khadija Rerhou Rantell,t
Saaeha Rauz,u,ah Ameeta Retzer,v,ai Steven Rizk,w Lynne Wagner,x Maxime Sasseville,y Lesley K. Seymour,r Harald A. Weber,z Roger Wilson,aa
Melanie Calvert,b,ab,ac,ad,ae and John Devin Peipertf
a
Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK
b
Centre for Patient-Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham,
Birmingham, UK
c
Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27514, USA
d
AstraZeneca, Oncology Research and Development, Gaithersburg, MD, USA
e
Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD, USA
f
Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
g
Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA
h
Leeds Institute for Medical Research, University of Leeds, St James’s University Hospital, Leeds, UK
i
RTI Health Solutions, Patient Centered Outcomes Research, Research Triangle Park, NC, USA
j
NU Cancer, Newcastle University, Newcastle upon Tyne, UK
k
Princess Alexandra Hospital, Cancer Services, Brisbane, Queensland, Australia
l
Merck KGaA, Darmstadt, Germany
m
Federal Agency for Medicines and Health Products (FAMHP), Brussels, Belgium
n
LUNGevity Foundation, Bethesda, MD, USA
o
Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA
p
Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK
q
The Association of the British Pharmaceutical Industry, UK
r
Canadian Cancer Trials Group (CCTG), Kingston, Ontario, Canada
s
Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium
t
Medicines and Healthcare Products Regulatory Agency (MHRA), UK
u
Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, UK
v
Centre for Patient Reported Outcomes Research (CPROR), Institute of Applied Health Research, University of Birmingham, Birmingham, UK
w
Veloxis Pharmaceuticals, Cary, NC, USA
x
University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA
y
Health Canada, Ottawa, Ontario, Canada
z
Pfizer Oncology, Global Medical Affairs/Early-Stage Development, Zug, Switzerland
aa
Cancer Research Advocates Forum UK, Sarcoma Patient Advocacy Global Network, UK
ab
National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC), University Hospital
Birmingham and University of Birmingham, Birmingham, UK
ac
NIHR Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK
ad
NIHR Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK
ae
Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK
af
Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA
ag
University of Queensland, Faculty of Medicine, Australia
ah
Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
ai
National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

Summary eClinicalMedicine
2024;76: 102838
Early phase clinical trials provide an initial evaluation of therapies’ risks and benefits to patients, including safety and
tolerability, which typically relies on reporting outcomes by investigator and laboratory assessments. Use of patient- Published Online 24
September 2024
https://doi.org/10.
reported outcomes (PROs) to inform risks (tolerability)
1016/j.eclinm.2024.
*Corresponding author. Clinical Trials and Statistics Unit, The Institute and benefits (improvement in disease symptoms) is more
of Cancer Research, London, SM2 5NG, UK. 102838
common in later than early phase trials. We convened a
E-mail address: christina.yap@icr.ac.uk (C. Yap).

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 Health Policy

two-day expert roundtable covering: (1) the necessity and feasibility of a universal PRO core conceptual model for early
phase trials; (2) the practical integration of PROs in early phase trials to inform tolerability assessment, guide dose
decisions, or as real-time safety alerts to enhance investigator-reported adverse events. Participants (n = 22) included:
patient advocates, regulators, clinicians, statisticians, pharmaceutical representatives, and PRO methodologists working
across diverse clinical areas. In this manuscript, we report major recommendations resulting from the roundtable
discussions corresponding to each theme. Additionally, we highlight priority areas necessitating further investigation.

Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

Keywords: Patient-reported outcomes; Dose-finding; Phase I; Phase II; Early phase trials; Tolerability; Patient-centred
clinical development; Quality of life; Trial designs

Introduction decisions. A recent review (2016–2022) of published

Early phase (I/II) clinical trials advance clinical devel- dose-finding oncology trials with PRO analysis found
opment by providing crucial insights into dose selection that PROs influenced dose decisions in only 11.4% (4/
for the investigational therapy and into adverse events 35) of trials. Three trials utilised PROs only at the end to
(AEs) arising from different dosages, the interaction confirm the tolerability of the recommended phase 2
with the human body, and to capture early signals, dose. Notably, only one 3 + 3 trial formally incorporated
indicating benefits for patients.1–4 Assessment of a PROs to inform interim dose decisions, defining a
therapy’s safety and tolerability has predominantly specific PRO score increase as a DLT.13 Since 2020, the
relied on clinical investigator reporting and interpreta- novel dose-finding model-based and model-assisted de-
tion using the Common Terminology Criteria for signs PRO-CRM, U-PRO-CRM, and PRO-ISO design
Adverse Events (CTCAE) or other AE grading ap- have emerged, formally incorporating PROs.14–16 These
proaches that do not include direct reports from pa- designs integrate patient- and investigator-reported in-
tients. A review of ClinicalTrials.gov from 2007 to 2020 formation to guide interim dose assignment decisions
showed that PROs were included in only 5.3% (548/ and provide the final dose recommendations. They can
10,372) of trials, though their use increased over time, also be extended to capture cumulative or late-onset
primarily (89.6%) as secondary outcomes.5 Compared to toxicities, as demonstrated in the TITE-PRO-CRM
patients, clinicians significantly underreport symptom- design.17 These advancements optimise dose-finding
atic AEs.6–9 AEs that are challenging to observe (e.g., by incorporating patient voice on treatment tolerability,
fatigue) may be inadequately characterised without which is crucial for targeted therapies and immuno-
direct input from patients, and the cumulative impact of therapies intended for long-term administration.
multiple AEs on the patient is not adequately captured Despite limited use in dose-finding oncology trials, a
by individual AE reporting.10 These deficiencies may global survey found widespread endorsement from over
lead to inaccurate tolerability assessment, incorrect or 100 stakeholders regarding the use of PROs for
sub-optimal dose-selection, sub-optimal risk-benefit assessing tolerability and informing dose selection.18
evaluation, and, ultimately, delays or failures in the However, a significant barrier identified for PRO
clinical development pathway. Moreover, because PROs implementation was the absence of guidance on which
can be captured in real-time between study visits, PROs should be utilised and implemented. Recent ini-
omitting them from early phase trials is a missed op- tiatives such as the FDA Optimus Project,19 aiming to
portunities to efficiently capture AEs as they arise and reform dose optimization in oncology,20,21 and the
intervene with patients to manage AEs, develop sup- Methodology for the Development of Innovative Cancer
portive and risk minimisation measures, or collect crit- Therapies guidelines,22 highlight the growing recogni-
ical information to plan for subsequent trials.11 tion of the value of incorporating PROs in early phase
Historically, dose-finding trials in oncology have trials. While the US FDA has advanced a core set of
focused on dose-limiting toxicity (DLT) identified from PROs for later phase cancer trials, no such recommen-
cycle 1 data, especially in trials utilising rule-based de- dations exist for early phase trials,23 though EMA guid-
signs like 3 + 3.12 The 3 + 3 design involves adminis- ance recommends considering PROs early in the
tering a dose to three patients at a time, escalating the development programme, particularly if there is a need
dose if there are no or minimal toxicities, and deter- to develop a dedicated instrument.24
mining the Maximum Tolerated Dose (MTD) based on This article discusses integrating PROs in early
observed DLTs within a defined time window. The phase exploratory trials, encompassing phase I dose-
identified MTD is usually the recommended dose in escalation studies and first-in-human investigations, as
subsequent testing. These designs have infrequently well as dose expansion, dose optimisation, seamless
capitalized on the potential for PROs to enhance dose phase I/II and phase II trials. Drawing insights from an

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expert roundtable, the paper explores two main themes:

Box 1.
the feasibility of establishing a universal PRO core
Key questions for each theme
conceptual model for assessing tolerability in early
phase trials across various disease settings and the
utility of PROs in guiding dose decisions and acting as Theme 1
real-time safety alerts. The need and feasibility of establishing a universal set of PRO
core concepts for tolerability assessment:
• Is it feasible and is there a need to develop a PRO Core
Methods Outcome Set (COS) to assess tolerability in phase I and II trials?
On November 30th and December 1st, 2023, we • If yes, would there be major differences between the COS
organised two half-day expert virtual roundtable meet- needs for:
ings. We invited representatives from key stakeholder ◦ Phase I and phase II? How?
groups to ensure diverse range of perspectives and ◦ Oncology and non-oncology trials? How?
relevant expertise, including individuals recognised for
their publications or expertise in PROs and/or early Theme 2
phase trials. This included patient advocates, regulators, Practical considerations for incorporating PROs in trial design for
experienced clinical trialists, pharmaceutical industry tolerability assessment:
representatives, and PRO methodologists. One partici-
pant coded as a PRO methodologist is a biostatistician • How and for what purpose should PROs be used in early phase
who works on oncology trials. Participants with both settings?
oncology and non-oncology experience were repre- Key prompts
sented. Pre-meeting materials, detailing objectives and ◦ How should PROs be used to guide trial design, whether for
key questions, were sent to participants beforehand. dose escalation, dose optimisation, or general tolerability
Before exploring each theme, the joint hosts (CY, JDP, assessment to inform PRO strategy in later phase trials?
LA and MC) presented the following topics: 1) General ▪ Interim vs end-of trial analysis (and if they should be
concepts of phase I and II trials, covering research analysed formally or descriptively)
questions, participants, and trial designs; 2) Defining ▪ Real time reporting and response (utilising PROs to
inform adverse event grading or independent PRO
treatment tolerability from the patient’s perspective,25
assessment)
including introduction of the US FDA Core Set of ▪ Standardised vs ad hoc reporting
PROs for use in Cancer Trials.23 The presenters • What should be the role of PROs in regulatory decision-
acknowledged that much of the existing evidence orig- making in early phase trials?
inated from oncology studies but emphasised our
intention to assess applicability across disease settings.
The presentation also included key questions to
facilitate discussion for each theme, summarized in Box
participants included one patient, two academic clinical
1.
trialists, one PRO researcher/oncology clinician, and
The hosts led the discussions, starting with key
one pharmaceutical company representative. Since they
questions and using prompts to guide if needed.
did not participate in the roundtable sessions, they did
Spontaneous, unguided responses were encouraged.
not vote. They provided critical reviews of roundtable
Participants who did not offer spontaneous input were
decisions during the manuscript review. We note that
called on to increase participation representation. Sur-
the participant count varied between the two days of
vey questions were administered via Zoom to quantify
roundtable discussions, and the number of responses
agreement with key points during the discussions. Non-
differed across various questions because not all par-
presenting hosts took notes, which were compared to
ticipants voted on every question. This variation arose as
aid in summarizing the discussion. The focus was on
some participants joined later or had to leave earlier,
areas of consensus and where no consensus could be
while others encountered occasional connectivity issues.
reached. The protocol for these activities was submitted
Below, we summarise major points emerging from the
to the Northwestern University (USA) ethics board and
roundtable discussions, stratified by theme.
deemed not to be human subjects research
(#STU00220530).
Patient advocate 2 (9%)
Results Regulator 4 (18%)
Of 32 invited experts to the two-day virtual meeting, 22 Clinical trialist 5 (23%)
participated in the discussions and provided feedback Pharmaceutical representative 4 (18%)
on the draft manuscript (Table 1). Five who were unable Patient-reported outcomes methodologist 7 (32%)
to attend also provided input and feedback, while five
Table 1: Expert roundtable participants (N = 22).
did not participate at all. The five non-attendee

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Theme 1: model of PRO concepts to assess one patient advocate remarked that participation in early
tolerability in early phase trials phase trials may be an emotional experience for pa-
Overall benefits and challenges tients, and that PROs may play an important role in
Participants expressed strong support for using PROs to capturing such experience and its impact on treatment
assess tolerability of new therapeutic agents in early tolerability and acceptability.
phase trials and believed that PRO data could enhance Participants also highlighted challenges in imple-
risk-benefit assessments. Potentially beneficial uses of menting PROs in early phase trials. They noted that
PROs in phase I trials included aiding clinicians in AE communication between departments responsible for
reporting and gathering early information on treatment- late phase studies (which typically have more extensive
emergent AEs to inform future dosing strategies. The PRO expertise) and early phase studies may be hindered
latter benefit was deemed particularly crucial to mini- by existing structural barriers. In addition, phase I trial
mise dose modification, interruption, or early treatment programs’ strong focus on advancing the experimental
discontinuation due to tolerability and safety concerns treatment to phase II and the high failure rate of new
in later phase trials. Moreover, since PROs can be drugs may serve as disincentives to include PROs in
collected outside clinic visits as AEs occur, they may phase I studies.27 There was also acknowledgement that
better characterise AEs than retrospective reports made some phase I studies may include healthy volunteers
in study visits in clinic. These advantages also apply to instead of patients, entailing a somewhat different set of
phase II trials. Additionally, patient-reported tolerability PRO concepts. Finally, in first-in-human trials, the
in phase I trials can contribute to dose optimisation and relevant AEs may not be known. One participant noted
scheduling for future testing.14,19,22,26 Participants also that cancer trials funded by the National Cancer Insti-
suggested that PROs in phase II trials would provide tute and conducted by cooperative trials groups in the
critical formative data to support PRO strategies in later US do not receive reimbursement for implementation
phase trials, including measure selection, assessment of PROs in Phase II trials unless they are randomised.28
schedule, and sample size determination. More broadly, Fig. 1 summarizes the benefits and challenges

Fig. 1: Benefits and challenges.

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participants attributed to PRO integration in early phase outside of oncology, though there is growing interest.
trials. In addition, though the potential to add to patient When asked whether a common guidance should be
burden with PRO assessments was mentioned, a patient developed for oncology and non-oncology trials, only
advocate noted that the benefit of PROs in early phase 31% (5/16) responded yes. However, despite acknowl-
trials would outweigh the burden of completing them. edging different trial cultures, participants felt that the
They emphasised the importance of involving patients central PRO concepts in oncology would also likely be
and obtaining their input at early planning and trial relevant in non-oncology settings. They acknowledged
design stages on integrating PROs.18,29 that specific trials may require more tailored ap-
proaches, suggesting a common core with “add-on” sets
Need and feasibility of a single conceptual model for specific clinical settings.
When asked “Is it feasible and is there a need to
develop a PRO core outcome set (COS) to assess Recommendation 1. Considering these benefits, chal-
tolerability in phase I trials?”, 84% (16/19) of partici- lenges, and perceived feasibility, we recommend pro-
pants agreed that it would be feasible to identify and moting PRO collection in phase I and phase II trials.
include a minimum set of PROs in phase I trials. Key actions in these settings include fostering collabo-
Among those answering “no” (n = 3), the rationale was ration between early and late-stage therapeutic devel-
that institutional barriers may reduce feasibility of opment programs, educating and raising awareness
implementing PROs though they noted that it would about the importance of PRO integration in early phase
be feasible in the future. When asked the same ques- trials, involving patients and advocacy groups in early
tion about phase II trials, 95% (18/19) agreed it would phase trial designs integrating PROs, and encouraging
be feasible. funders to allocate targeted funding for early phase trials
to prioritize PRO collection inclusion. Future work
Shared vs separate guidance for phase I and phase II could involve investigating and developing guidance for
When participants were asked whether there would be a PRO COS, either shared or separate, for phase I and II
major differences in the PRO needs between phase I trials, as well as in both oncology and non-oncology
and phase II, 44% (7/16) said yes. Participants settings (Table 2).
mentioned that the PRO-related objectives for phase I
would likely be exclusively focused on tolerability, Suitability of the FDA core PROs in oncology for early phase
whereas phase II trials may encompass an additional trials
focus on collection of data to inform both risks and Given the general agreement that a conceptual model to
benefits, which may increase the relevance of PROs guide use of PROs in early phase trials was feasible, we
capturing disease-related symptoms in phase II trials. In considered whether the FDA Core PRO concepts would
contrast, phase I trials involving healthy volunteers may fit this need. In 2021, the US FDA published their draft
require a somewhat different set of concepts, where guidance document, Core Patient-Reported Outcomes in
disease symptoms would not be relevant. Cancer Clinical Trials Guidance for Industry.23 This
guidance identified core PRO concepts for assessment
Shared vs separate guidance for oncology and non-oncology in cancer trials, including disease related symptoms,
settings symptomatic AEs, overall side effect impact, physical
Participants discussed whether a single PRO core function, and role function (Fig. 2). An earlier version of
outcome set would be applicable in oncology and non- these core concepts without overall side effect impact
oncology settings. Twelve discussion participants and role function was registered with the COMET
(60%) primarily worked in oncology setting. An Initiative31 and published.32 Among the core PRO con-
oncology pharmaceutical representative noted that some cepts, symptomatic AEs, overall side effect impact, and
phase II oncology trials could provide pivotal results for physical function can be considered directly relevant to
regulatory approval, highlighting the potential for PROs tolerability assessment, while role function may be
in phase I trials to offer formative data for phase II considered indirectly relevant. The FDA PRO Core
design. Additionally, PROs could support cost- concepts were not designed for early phase trials, but
effectiveness analyses relevant for reimbursement. the included concepts were deemed to be very likely
There was also acknowledgement that regulators within relevant to capturing tolerability in early phase trials.33
and outside oncology seek PRO data to support risk- Participants reviewed the FDA Core PROs in
benefit assessment,24 particularly in the US where the oncology and supported their use in early phase trials,
21st Century Cures Act, passed in 2016, requires reports considering them suitable for both phase I and II trials
of patient experience with drug submissions.30 Phar- as a starting point. When asked, “What are the mini-
maceutical representatives working in non-oncology mum set of core concepts which should be included
investigational therapy development programs noted within phase I/II trials (please tick all which apply)”
that tolerability as a concept is less commonly used (asked separately about phase I and II) and given a

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therapy and disease. Despite this, there was agreement

Recommendations Actions
that all concepts would be relevant in most therapeutic
1. Promote PRO collection in early phase I Foster collaboration and communication areas. Finally, discussions emphasized the need for
and phase II trials between early and late-stage therapeutic
development programs to facilitate the further specification of endpoints depending on
integration of PROs in phase I and II trials, which whether descriptive or decision-informing analyses are
would in turn inform future utilisation in later planned.
stage trials.
Educate and raise awareness among stakeholders
about the significance of PROs in early phase I Recommendation 2. Adopt the FDA core PRO concepts -
and II trials, emphasising the value of integrating overall side effect impact, symptomatic AEs, physical
PRO objectives alongside conventional objectives function, role function, and disease symptoms–across
to enhance research quality and patient-
centricity. oncology and non-oncology settings for phase II trials.
Involve patients and patient advocacy groups in For phase I trials, prioritize a smaller core set using the
the design and conduct of early phase trials, FDA core PRO concepts as a basis, that include
gathering their input on the selection of PRO the concepts of overall side effect impact and symptomatic
measures/items and ensuring that their
perspectives are captured in the research process.
AEs.
Encourage funders to allocate targeted funding
for early phase trials that prioritise PRO Theme 2: practical recommendations for
integration in early phase study designs integrating PROs in early phase trials
2. Adopt the FDA core PRO concepts as an initial For Phase I: overall side effect impact, PROs influence CTCAE (real-time) vs independent PRO
step in selecting PRO measures to be collected. symptomatic adverse events
assessment
For Phase II: overall side effect impact,
symptomatic adverse events, physical function,
The panel deliberated on two approaches for phase I and
role function, and disease symptoms as a core II jointly: (1) using PROs capturing AEs and/or overall
outcome set across oncology and non-oncology side effect impacts to inform investigator-reported AE
settings. grading, potentially by promptly signalling red flags
Develop PRO core outcome sets for phase I and II
(such as severe PRO scores) to investigators in real-time,
trials, and consider appropriateness for oncology
and non-oncology settings. or (2) assessing both investigator and patient reports
3. Conduct additional research into multiple independently, such that PROs complement but do not
aspects of integrating PROs into early phase influence investigator-reported AE gradings. The panel
trials: had the option to select either or both approaches and
a. Feasibility and validity of implementing of Conduct pilot studies that determine feasibility
voted 13/17 for (1) and 12/17 for (2) (Fig. 3).
PROs in early phase trials across differing trial settings, implementation
challenges potentially encountered by clinical Both approaches were considered viable, contingent
teams when PROs are implemented in real time upon specific circumstances. The feasibility of the first
and ad hoc, with or without real-time alerts. approach would depend on operational and logistical
b. Using PROs to inform interim trial decisions, Conduct additional consensus-building work considerations specific to the organization, as well as the
end-of-trial analysis, and CTCAE grading, with diverse stakeholders, including clinical
considering descriptive and comparative PRO trialists and methodologists, patients, PRO study team’s willingness and resources to manage real-
analyses researchers, and regulators time flagging of PROs for safety monitoring. The sec-
ond approach may be preferable in cases where it is
Table 2: Recommendations and actions toward integrating PROs in early phase trials. desirable to maintain independence between the two
outcomes without any potential influence. For instance,
in sensitive topics where there could be a strong social
choice of the concepts from the FDA Core PROs as desirability bias influencing patient reporting if results
options, there was high agreement that symptomatic were shared with clinicians. Additionally, patients’
AEs and overall side effects impact summary should be reporting behaviour may be altered as they are often
included in both phase I and II (Fig. 3). Fewer partici- concerned that reporting severe symptoms may result to
pants prioritized physical function, role function, and changes to their dosage, dose interruptions or treatment
disease-related symptoms for phase I trials, but the withdrawal, potentially altering their reporting
endorsement rate for all FDA Core PROs was high for behaviour.34
phase II trials. Participants acknowledged key benefits
of starting with the FDA Core PROs for Cancer Trials Interim vs final analysis
include its flexibility and ease of tailoring to different The panel discussed whether PROs should guide
study needs, the capture of key concepts with only 1–2 interim decisions, or be reserved solely for final analysis.
items (questions), and its existing use in FDA-reviewed Participants strongly agreed PROs should play a role in
phase III trials. They also identified areas requiring decision-making in general, though refinement, clarity,
additional research for implementing FDA Core PRO and consensus of when to do so is required. For dose-
concepts in early phase trials. These include more finding trials, no consensus was reached on whether
granular examination of the importance of tolerability in PROs should guide dose-decisions at both the interim
different settings depending on the investigational and final assessments or only at the final analysis, with a

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Fig. 2: Core set of PRO conceptual model adapted from US FDA guidance.

vote distribution of 50%–50%. For phase II trials, the the ability of ad hoc PRO reports to have clinical value,
majority (88.2%) felt that PROs should be used at the though this would require testing. No formal vote was
final analysis, while for trials utilising adaptive designs, conducted on this matter.
58.8% supported using PROs to guide interim decisions
(Fig. 3). Participants noted that utilising PROs to guide Regulators’ perspectives
interim decision making would be beneficial. However, Our regulatory participants emphasised the importance
they expressed concerns about the logistical challenges, of adequately collecting PROs data and gaining a clearer
particularly in situations where decisions need to be understanding of their potential value in decision-
made rapidly, such as patient assignments to the next making. They recommended starting with a more con-
dose level in dose-finding trials. servative, primarily evidence-generating approach
before proceeding to more formal integration, such as
Formally vs descriptively interim decisions. They strongly support incorporating
The panel further deliberated if PROs should be incor- the patient voice early on, particularly regarding patient-
porated formally within the trial design, or be used reported tolerability, which can impact dosing, and
descriptively only to inform decision making. No compliance, which would add value to clinical develop-
consensus was reached on whether the incorporation of ment they also highlighted the need to build the evi-
PROs for this purpose, should be formal vs descriptive dence base for use in early phase settings to enable
use, with a vote distribution of 44%–56% for dose- regulatory acceptance. Nonetheless, they recognised the
finding trials and 59%–41% for phase II trials (Fig. 3). value of using information in real-time or on an interim
basis.
Standardised vs ad hoc reporting
In this context, standardised reporting refers to protocol- Recommendation 3. Conduct additional research into
defined time-points for PRO assessments, whereas ad multiple aspects of integrating PROs into early phase
hoc reporting refers to additional PRO assessments trials, including their feasibility, validity, and their use
triggered by trial participants experiencing a change in in informing decisions across different study designs.
outcomes. The concept of ad hoc reporting was recog- Key actions to address these recommendations include
nised as still exploratory with potential advantages conducting pilot studies to determine feasibility and
particularly in early phase settings, although its feasi- validity of PRO data collection in phase I and II trials
bility remained uncertain. Previous research by Basch across different trial settings and approaches to PRO
and colleagues demonstrated that real-time alerts and implementation, similar to PRO feasibility assessments
monitoring led to reduced hospitalizations and performed in the real world setting.37 For example,
improved survival.35,36 Though somewhat different than piloting differing assessment schedules, implementing
ad hoc reporting, these results may indicate promise for real time alerts, and ad hoc reporting are needed before

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THEME ONE

Question Results Agreement

Feasibility and need to There is both a need and it is

develop core outcome feasible to develop a PRO COS
set. 16/19 to assess tolerability in both
Yes
18/19 Phase I and Phase II trials.

Response
Is it feasible and is there a Phase I
need to develop a PRO
3/19 Phase II
COS to assess tolerability No
in trials 1/19

0 20 40 60 80 100
Percentage (%)

Shared guidance No agreement was reached on

whether there is a major
(1) Would there be
1 7/16 difference in PRO needs
Statement

major differences in
between Phase I and Phase II
the PRO needs
trials.
between Phase I
and Phase II? 2 5/16
(2) Should a common
No agreement was reached on
guidance be
whether a common guidance
developed for 0 20 40 60 80 100
should be developed for
oncology and non- Pecentage agreed (%)
oncology and non-oncology
oncology trials?
trials.

Question Results Agreement

For Phase I trials, participants

Disease-related 3/14 endorsed the inclusion of
symptoms 14/14 symptomatic adverse events
Participants’ and overall effect summary
Endorsement of Symptomatic adverse 14/14 concepts in a minimum PRO
Concepts for Inclusion in events 14/14 set for Phase I trials.
Concepts

a Minimum PRO Set for

They also agreed that disease-
Early Phase Trials Overall side effect 13/14
summary 13/14 Phase I related symptoms and role
function should not be used.
Phase II
5/14 No agreement was reached on
Physical function
12/14
the use of physical function.
1/14 For Phase II trials, participants
Role function
10/14 endorsed the inclusion of
disease related symptoms,
0 20 40 60 80 100
symptomatic adverse events,
Percentage endorsed (%) overall effect summary,
physical function and role
function concepts in a
minimum PRO set for Phase II
trials.

Fig. 3: Poll questions for participants for themes one and two. For illustrative purposes, high level of agreement (≥70% of participants)
indicative that consensus is reached are coloured in green, and the rest are coloured in orange (<70% of participants).

specific study design recommendations can be made. To reports from patients and clinicians in tolerability
refine how PROs can support decisions about investi- assessment is needed.
gational therapy tolerability, and/or dose-finding/
optimization, additional consensus building activities
with diverse stakeholders are needed. For example, Discussion
questions regarding whether PRO data should support PROs are valuable for assessing risks and benefits of
AE grading in real-time, or only utilized at the trial’s emerging treatments in clinical trials,38 but guidance is
conclusion, and whether PRO data should be summar- limited for early phase trials. To address this, an inter-
ised descriptively or formally guide decision-making, re- national group of experts representing multiple stake-
quires further attention (Table 2). Additionally, work to holder types participated in a two-day roundtable and
understand how to weight the relative importance of identified ways that PROs can generate substantial value

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THEME TWO

PRO influence CTCAE There is agreement that

(real-time) vs either approach could be
Independent PRO used.
1 13/17
Assessment
Statement

What do you think is

Participants considered it
suitable? Select all which
suitable to use PROs in real
apply.
2 12/17 time to capture symptomatic
(1) Use PROs in real- adverse events and/or overall
time to capture side effect to inform CTCAE
symptomatic 0 20 40 60 80 100 grading.
adverse events Pecentage agreed (%)
and/or overall side
effect to inform Participants also considered
CTCAE grading. it suitable to use PROs
independently to assess
(2) Use PROs in a patient-rated intolerability
more formal way alongside investigator-rated
(independently) to CTCAE grading.
assess patient-
rated intolerability
alongside
investigator-rated
CTCAE grading.
Interim vs Final Analysis No agreement was reached
For each cohort 9/18 on whether PROs should be
Should PROs be used to (interim & final) used to guide dose decisions
Timepoint

guide dose decisions in at final and/or interim

At the end of the trial 9/18
dose-finding trials? (final) analysis in dose-finding trials.
Phase I
Never 0/18

0 20 40 60 80 100
Percentage agreed (%)

Should PROs be used in Participants endorsed the

Phase II trial design to use of PROs at the final
guide decision-making? Interim (for adaptive
design)
10/17 analysis to guide decision
Please select all that making in Phase II trials.
apply.
Timepoint

No agreement was reached

Final analysis 15/17 on whether PROs should be
Phase II used at interim analysis to
guide decision making in
Phase II trials.
Never 0/17

0 20 40 60 80 100
Percentage agreed (%)

Formally vs No agreement was reached on

Descriptively whether PROs should be used
8/18
Formal decision making for formal decision making or
10/17
Should PROs be used…
Anlayse PROs

Phase II trials.
10/18
Descriptively
7/17 Phase I
Phase II
0/18
Never
0/17

0 20 40 60 80 100
Percentage agreed (%)

Fig. 3: Continued.

in both phase I and II trials. Based on these discussions, Advancing PRO use in early phase trials will require
we generated recommendations for implementing more pilot and demonstration projects. To our knowl-
PROs in early phase trials and highlighted key areas for edge, few prospectively designed studies have explored
future research where consensus was lacking. how PROs might affect AE assessment in early phase

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 Health Policy

settings.39 Veitch and colleagues collected patient-rated assessment, including specific PRO measures.41 An
AEs using the PRO-CTCAE along with standard physi- early phase trialist wishing to include PROs should
cian rated AEs in a phase I trial of solid tumor patients, identify which of the core PRO concepts recommended
though the PRO assessments were not used to inform here are most appropriate for their study, then select
the physician-rated AEs.9 This study found considerable specific PRO measures accordingly. The FDA’s Guid-
disagreement between PRO and non-PRO AE ratings, ance23 identified the Functional Assessment of Cancer
indicating the strong potential for PRO-informed AE Therapy (FACIT) GP5 item (“I am bothered by side ef-
ratings to differ from a purely physician-rated approach. fects of treatment”) and the European Organisation for
Ideally, a prospective study comparing PRO-informed Research and Treatment of Cancer (EORTC) Q168 (“To
and non-PRO-informed physician-rated AEs could be what extent have you been troubled with side-effects
conducted to determine the feasibility and impact of this from your treatment”) as options for capturing overall
approach. A current trial is examining whether PROs side effect impact, and the PRO-CTCAE, and FACIT
can improve the reliability of AE grading, and the results and EORTC item libraries as options for capturing
are expected to be informative for PRO implementation symptomatic AEs. Several PRO measurement systems
in early phase trials.40 In addition, greater specification and item libraries, including cancer specific FACIT and
of how PROs would be used to inform AE ratings and EORTC, but others including the Symptom Burden
decision-making is required. For example, the PRO and Questionnaire42 and PROMIS43 offer PRO measures of
physician ratings may be made separately and then physical function, role function, and disease symptoms.
evaluated through a formal or informal review process. Overall side effect impact PROs are likely relevant
Finally, the potential advantages and challenges of across many different toxicity profiles and are typically
implementing PROs in more complex designs testing captured with a single overall question, leading to po-
multiple hypotheses among diverse subgroups with tential efficiencies in early phase settings where a
small sample sizes (e.g., basket and umbrella trials) re- treatment’s full AE profile is unknown. While including
quires further exploration. questions for all potential toxicities can increase patient
One of the roundtable’s goals was to determine burden,41,44,45 focusing on common toxicities (e.g.,
whether separate guidance would be required for nausea, diarrhoea, and fatigue in oncology) strikes a
oncology vs non-oncology trials. Though only one dis- good balance. Addition of a free text option can also
cussion topic within Theme 1 specifically addressed provide valuable insights into unanticipated side ef-
oncology vs non-oncology trial settings, we acknowledge fects.46 A comprehensive PRO strategy with clearly
that the majority of participants (60%) primarily worked defined PRO objectives (e.g., using the estimand
in oncology setting. Some participants noted that the framework)47 would include specification of assessment
concept of tolerability, especially as it applies to PROs, is timepoints, administration approaches (e.g., paper vs
most familiar in oncology presently. In addition, a key electronic), and ethical agreements.11,34,48
take-away of our work is agreement on primarily Our work has strengths and limitations. Key
considering core PRO concepts, adapted from the FDA strengths include integration of multidisciplinary
guidance for registration trials for anti-cancer therapies, expertise, fostering rich contextual discussions and
as the basis for a minimum set of PRO concepts for diverse and nuanced perspectives, and an efficient and
early phase trials. This approach is particularly relevant flexible roundtable approach, allowing dynamic discus-
to early phase cancer trials, as it provides a consistent sion between participants, immediate feedback in
framework for examining PROs across different trial response to key questions, and the ability to pursue
phases. By establishing this link between early and late emerging topics as they arose. Additionally, we
phase trials, researchers can gain valuable insights into employed structured polls to quantify opinions about
the patient experience and the impact of cancer treat- key issues from participants on the spot. Moreover, a
ment over time. We note that all the recommendations significant strength was patient involvement, including
made in this paper are relevant for considering in both those with extensive experience and recent lived expe-
oncology and non-oncology trials; however, further riences of different chronic diseases with treatment
evaluation may be necessary before applying the FDA burden. Limitations included having predominantly
core PRO conceptual framework to non-oncology participants from the US, Europe and Canada (with only
settings. one participant from Australia), potentially limiting
Investigators from an academic cancer centre previ- global representativeness despite reflecting current
ously developed a phase I trial-tailored PRO assessment, leadership in the field. The broad focus on both
bolstering optimism about the feasibility of generating a oncology and non-oncology may not fully capture the
PRO core for this setting. Retzer and colleagues laid-out diverse needs and priorities of specific clinical areas that
a multi-stage strategy for PRO assessment in early phase are not represented. Moreover, the joint hosts presented
trials which specifies identifying aims, objectives, and an introduction to the discussion topics and existing
concepts of interest as the first step, after which key research, which focused largely on oncology since that
outcomes are identified related to the rationale for field has been the primary area of focus in use of PROs

10 www.thelancet.com Vol 76 October, 2024

 Health Policy

in early phase trials to date. Though this presentation manuscript with input from MC and OLA. EA, CY and JDP handled
could have influenced participants’ responses, it was data curation, analysis and visualisation. EA and CY have access to the
raw data. All authors contributed to the roundtable discussions or pro-
necessary to inform the discussion. Importantly, the
vided feedback. All authors critically reviewed the manuscript and
joint hosts deliberately refrained from expressing their approved the final version.
own preferences or views on a preferred approach.
Other limitations included the absence of more struc- Declaration of interests
tured processes with more participants like the Delphi C.Y. has received consulting fees from Faron Pharmaceuticals and an
method or nominal group technique, which might affect honoraria from Bayer.
O.L.A. reported receiving grants from the National Institute for
the rigour and reliability of the recommendations, and
Health and Care Research (NIHR) Birmingham Biomedical Research
the potential influence of strong opinions on group’s center, NIHR Applied Research Collaboration West Midlands, NIHR
consensus. To minimise this potential source of bias, we Blood Transplant Research Unit (BRTU), UK Research and Innovation
anonymized the polls for key recommendations. This (UKRI), Health Foundation, Gilead, Anthony Nolan, GlaxoSmithKline,
roundtable discussion, involving multidisciplinary in- Merck, and Sarcoma UK. OLA declares personal fees from Gilead Sci-
ences Ltd, Merck, and GlaxoSmithKline, Innovate UK outside the sub-
ternational experts, is an initial step in addressing the mitted work.
emerging field of PROs in early phase trials. To support E.B. has received payments as a scientific advisor for Navigating
comprehensive consensus-based recommendations, we Cancer, AstraZeneca, Resilience, N-Power Medicine, and Verily.
must first elicit input on major concepts, explore key J.B. is an employee of AstraZeneca, with ownership interest in
AstraZeneca and is engaged by Evinova, a separate healthtech business
points to address, and expand the evidence base. We
within the AstraZeneca group.
recognise the necessity for additional, more represen- A.H. has Research funding (paid to institution): Advancell, BMS, MSD,
tative consensus work, like a Delphi exercise using the Macrogenics, Tyra Biosciences, Janssen, Seagen, Aveo, Roche/Genetech;
EQUATOR approach for guidance generation. We plan Consulting (paid personally): MSD, Pfizer, Eisai, Astellas, Bayer.
to conduct a Delphi exercise in the near future, with P.K. has shares in Merck Healthcare KgaA and is a Full-time
employee of Merck Healthcare KgA.
some leading authors already working on related ini- B.K.K. has grants paid direct to organisation from AstraZeneca,
tiatives, including the development of a PRO core Boehringer Ingelheim, Bristol Myers Squibb, Jazz Pharma, Genentech,
outcome set49 and PRO analysis recommendations for Eli Lilly, Janssen, Takeda, Dachii Sankyo, Blueprint, Medicines, Janssen,
dose-finding oncology trials. Finally, though we had a Amgen, Seagen, Manta Cares and personal consultancy fees from Eli
Lilly, BMS, AbbVie, Shionogi.
diverse set of participants, we were unable to compare
H.M.K. has received grants unrelated to the work from the
responses to the polling questions by stakeholder group American Heart Association to Jansson; Agency for Healthcare
because the individual responses to each question could Research and Quality to Kenvue; National Institutes of Health to
not be linked to their respective stakeholder groups. Novartis; Centers for Medicare & Medicaid Services to Pfizer and
Since the expert roundtable meeting, an FDA work- Centers for Disease Control and Prevention. These grants and con-
tracts are unrelated to the work above and are through Yale University
shop has highlighted the value of assessing tolerability or Yale New Haven Hospital. Received consulting fees from Massa-
from the patient perspectives in early phase cancer tri- chusetts Medical Society (to Co-Editor, Journal Watch Cardiology);
als.50 This suggests that some regulatory agencies have UpToDate (as Section Editor) and Ensight (unpaid advisor). Payment
greater recognition of the importance of collecting PROs or honoraria for lectures, presentations, speakers’ bureaus, manu-
script writing or educational events would have received occasional
in cancer trials, as they have outlined ways that this
travel expenses and/or honoraria to speak at various educational/aca-
information will be considered in benefit-risk demic venues. Received travel expenses and/or honoraria to speak at
evaluation. various educational/academic venues. Stocks in Element Science and
In conclusion, integrating PROs in early phase trials Identifeye.
represents a critical next step in patient-focused clinical A.M. has served on advisory boards for Janssen Pharmaceuticals,
GSK, Merck Pharmaceuticals, Takeda Pharmaceuticals, MSD Pharma-
development and ensures that emerging treatments ceuticals, Faron Pharmaceuticals, Pfizer Pharmaceuticals, AZ, Genmab
reflect patients’ experiences and priorities. While PROs Pharmaceuticals and Immutep Pharmaceuticals. Has received hono-
are used to assess treatment tolerability in later phase raria from Chugai Pharmaceuticals, Faron Pharmaceuticals, Merck
trials, their application in earlier phase trials, where Pharmaceuticals, GSK, Seagen, Takeda Pharmaceuticals and Janssen
Pharmaceuticals. Has travel support from Amgen Pharmaceuticals and
tolerability and getting the dosing strategy right are vital,
Janssen Pharmaceuticals. Has received research funding from Astex
remains underdeveloped. The expert roundtable rec- Pharmaceutical, Merck Pharmaceuticals and MSD.
ommendations presented here will advance the ability to J.P. is a Patient representative on CCTG.
use PROs in early phase trials directly, or point to areas S.R. Research grants with Medical Research Council, NIH/NEI,
of additional research. Ultimately, alignment of inves- NIHR outside permitted work.
A.R. reported receiving grants from National Institute for Health
tigational therapy developers, regulators, and clinical Research (NIHR) Birmingham Biomedical Research Centre (BRC) paid to
trialists will be needed to realise this vision, and multi- University of Birmingham and has funding outside the submitted work
disciplinary efforts like ours provide a useful model for from NIHR, Birmingham City Council, ACCELERATE, Office of Health
achieving that. Disparity and Inequality. Support for attending meetings from
Outsourcing in Clinical Trials UK/Ireland as invited speaker. Honoraria
Contributors from Wellcome Sanger Institute Representative Research Strategy Advi-
CY, JDP, OLA and MC conceived the idea for the expert roundtable sory Group and ACCELERATE (Innovations for Children and Adolescents
discussion, prepared the materials and were responsible for investiga- with Cancer) International Patient-Reported Outcomes Working Group—
tion and methodology. CY and JDP wrote the first draft of the Core Group Member and Work-package Lead (unpaid).

www.thelancet.com Vol 76 October, 2024 11

 Health Policy

S.R. is employed by Veloxis Pharmaceuticals, Inc. Stock in the 9 Veitch ZW, Shepshelovich D, Gallagher C, et al. Underreporting
following companies: Bristol Myers-Squibb, Gilead Sciences, IGM Bio- of symptomatic adverse events in phase I clinical trials. J Natl
sciences, Merck & Co, Pfizer. Cancer Inst. 2021;113(8):980–988. https://doi.org/10.1093/jnci/
djab015.
L.I.W. has received consulting fees from Celgene/Bristol Myers
10 O’Connell NS, Zhao F, Lee J-W, et al. Importance of low- and
Squibb; Connect Multiple Myeloma registry, member Scientific Steering moderate-grade adverse events in patients’ treatment experience
Committee. and treatment discontinuation: an analysis of the E1912 trial.
L.K.S. reports funding to institution from AZ, Bayer, Roche, GSK, J Clin Oncol. 2024;42(3):266–272. https://doi.org/10.1200/jco.23.
Treadwell, REPARE, Novartis, Janssen, MERCK. Shares: AZ. 00377.
H.A.W. is employed by Pfizer AG, Switzerland and owns non-voting 11 Retzer A, Aiyegbusi OL, Rowe A, et al. The value of patient-reported
shares of Roche Ltd. outcomes in early-phase clinical trials. Nat Med. 2022;28(1):18–20.
M.J.C. is the Director of Birmingham Health Partners Centre for https://doi.org/10.1038/s41591-021-01648-4.
12 Postel-Vinay S, Collette L, Paoletti X, et al. Towards new methods
Regulatory Science and Innovation and Centre for Patient Reported
for the determination of dose limiting toxicities and the assessment
Outcomes Research and a National Institute for Health and Care of the recommended dose for further studies of molecularly tar-
Research (NIHR) senior investigator; has received funding from An- geted agents – dose-limiting toxicity and toxicity assessment
thony Nolan, European Regional Development Fund-Demand Hub and recommendation group for early trials of targeted therapies, an
Health Data Research UK, Gilead, GSK, Janssen, Macmillan Cancer European organisation for research and treatment of cancer-led
Support, Merck, NIHR, NIHR ARC WM, NIHR Birmingham BRC, study. Eur J Cancer. 2014;50(12):2040–2049. https://doi.org/10.
NIHR BTRU Precision and Cellular Therapeutics, UCB Pharma, UKRI, 1016/j.ejca.2014.04.031.
and UK SPINE; and has received consultancy fees from Aparito, 13 Alger E, Minchom A, Lee Aiyegbusi O, Schipper M, Yap C. Sta-
tistical methods and data visualisation of patient-reported outcomes
Astellas, Boehringer Ingelheim, CIS Oncology, Daiichi Sankyo, Gilead,
in early phase dose-finding oncology trials: a methodological re-
Glaukos, GSK, Halfloop, Merck, Patient-Centered Outcomes Research view. eClinicalMedicine. 2023;64:102228. https://doi.org/10.1016/j.
Institute, Pfizer, Takeda, and Vertex Pharmaceuticals Incorporated, eclinm.2023.102228.
outside of the submitted work. 14 Lee SM, Lu X, Cheng B. Incorporating patient-reported outcomes
The views and opinions expressed in this publication are those of in dose-finding clinical trials. Stat Med. 2020;39(3):310–325.
the individual co-authors and may not be understood or quoted as being https://doi.org/10.1002/sim.8402.
made on behalf of or reflecting the position of any organisation, com- 15 Wages NA, Lin R. Isotonic phase I cancer clinical trial design uti-
mittee, working party or group with which the co-authors are affiliated. lizing patient-reported outcomes. Stat Biopharm Res. 2024:1–10.
https://doi.org/10.1080/19466315.2023.2288013.
Acknowledgements 16 Alger E, Lee SM, Cheung YK, Yap C. U-PRO-CRM: designing
patient-centred dose-finding trials with patient-reported outcomes.
CY receives programmatic infrastructure funding from Cancer
ESMO Open. 2024;9(7):103626. https://doi.org/10.1016/j.esmoop.
Research UK (C1491/A25351) and ECMC (ECMCQQR-2022/100011) 2024.103626.
which supported this work. OLA, MA and AR were funded for this work 17 Andrillon A, Biard L, Lee SM. Incorporating patient-reported out-
by the NIHR Birmingham BRC (ref. NIHR203326, P.N.N.) The views comes in dose-finding clinical trials with continuous patient
expressed are those of the authors and not necessarily those of the enrollment. J Biopharm Stat. 2023:1–12. https://doi.org/10.1080/
NIHR or the Department of Health and Social Care. 10543406.2023.2236216.
18 Lai-Kwon J, Vanderbeek AM, Minchom A, et al. Using patient-
Appendix A. Supplementary data reported outcomes in dose-finding oncology trials: surveys of key
stakeholders and the national cancer research Institute consumer
Supplementary data related to this article can be found at https://doi.
forum. Oncologist. 2022;27(9):768–777. https://doi.org/10.1093/
org/10.1016/j.eclinm.2024.102838. oncolo/oyac117.
19 United States Food and Drug Administration. Project optimus:
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