Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Cancer Clinical Trial
Eligibility Criteria:
Patients with Organ
Dysfunction or Prior or
Concurrent
Malignancies
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2020
Clinical/Medical

Cancer Clinical Trial
Eligibility Criteria:
Patients with Organ
Dysfunction or Prior or
Concurrent Malignancies
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2020
Clinical/Medical

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
III. RECOMMENDATIONS.................................................................................................. 3
A. Patients with organ dysfunction ................................................................................................... 3
1. Renal function recommendations ..................................................................................................... 3
2. Cardiac function recommendations ................................................................................................. 4
3. Hepatic function recommendations ................................................................................................. 5
B. Patients with prior or concurrent malignancy ............................................................................ 5

Contains Nonbinding Recommendations
1
Cancer Clinical Trial Eligibility Criteria:
Patients with Organ Dysfunction or Prior or Concurrent
Malignancies
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. INTRODUCTION
This guidance is one in a series of guidances that provide recommendations regarding eligibility
criteria for clinical trials of drugs or biological products2 regulated by CDER and CBER for the
treatment of cancer.3 Specifically, this guidance includes recommendations regarding the
inclusion of patients with organ dysfunction or with prior or concurrent malignancies. This
guidance is intended to assist stakeholders, including sponsors and institutional review boards,
responsible for the development and oversight of clinical trials.
A clinical trial’s eligibility criteria (for inclusion and exclusion) are essential components of the
trial, defining the characteristics of the study population. Because there is variability in
investigational drugs and trial objectives, eligibility criteria should be developed taking into
consideration the mechanism of action of the drug, the targeted disease or patient population, the
anticipated safety of the investigational drug, the availability of adequate safety data, and the
ability to recruit trial participants from the patient population to meet the objectives of the
clinical trial. However, some eligibility criteria have become commonly accepted over time or
used as a template across trials without clear scientific or clinical rationale. Unnecessarily
restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and
1 This guidance has been prepared by the Oncology Center of Excellence, Center for Drug Evaluation and Research
(CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 For the purposes of this guidance, references to drugs and drug and biological products include drugs approved
under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products licensed
under section 351 of the Public Health Service Act (42 U.S.C. 262).
3 Topics of the other three guidances are related to eligibility criteria for patients with human immunodeficiency
virus, hepatitis B virus, or hepatitis C virus infections; for patients with brain metastases; and regarding minimum
age considerations for inclusion of pediatric patients.

Contains Nonbinding Recommendations
2
lead to trial results that do not fully represent treatment effects in the patient population that will
ultimately use the drug.4,5
Broadening cancer trial eligibility criteria can maximize the generalizability of trial results and
the ability to understand the therapy’s benefit-risk profile across the patient population likely to
use the drug in clinical practice and should be considered to avoid jeopardizing patient safety.
Trial design and methodological approaches are important considerations when enrolling a
broader population and are addressed elsewhere6,7 and are not addressed in this guidance because
the considerations are not specific to enrolling patients with organ dysfunction or prior or
concurrent malignancies.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. BACKGROUND
Patients with organ dysfunction are often excluded from clinical trials, regardless of knowledge
of the metabolic pathways and excretory routes of the investigational drug. The life-span of the
general population is increasing and thus includes increasing numbers of patients with co-morbid
renal disease, cardiac disease, and hepatic dysfunction. Additionally, as life-span of the general
population increases, a greater number of patients are anticipated to have prior or concurrent
malignancies. By excluding individuals from cancer clinical trials who have major organ
dysfunction or previous or concurrent cancers, trial recruitment may favor younger patients,
which may not be fully representative of the population for whom the drug will be indicated.
Designing cancer clinical trials that include patients with organ dysfunction and prior or
concurrent malignancies and including this information in the labeling promotes the safe and
effective use of these products across a broader patient population likely to use the drug in
clinical practice.
4 Beaver JA, Ison G, Pazdur R, 2017, Reevaluating Eligibility Criteria- Balancing Patient Protection and
Participation in Oncology Trials, NEJM, 376:1504-1505.
5 Kim E, Bruinooge S, Roberts S, et al., 2017, Broadening Eligibility Criteria to Make Clinical Trials More
Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement,
JCO, 35(33): 3737-3744.
6 See the draft guidance for industry Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria,
Enrollment Practices, and Trial Designs (June 2019). When final, this guidance will represent the FDA’s current
thinking on this topic. We update guidances periodically. For the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
7 Jin S, Pazdur R, Sridhara R, 2017, Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of
Investigational New Drug Applications in 2015, JCO, 35(33): 3745-3752.

Contains Nonbinding Recommendations
3
III. RECOMMENDATIONS
Thoughtful consideration should be given to the potential inclusion of patients with organ
dysfunction or prior or concurrent malignancies in cancer clinical trials. The following
recommendations for eligibility criteria for patients with organ dysfunction in cancer clinical
trials focus on renal function, cardiac function, and hepatic function. This guidance also includes
recommendations for eligibility criteria for patients with cancer who have prior or concurrent
malignancies.
A. Patients with organ dysfunction
When pharmacokinetics (PK) and major routes of elimination in humans are not well
understood, it is reasonable to enroll only patients with relatively preserved organ function
(primarily renal and hepatic) in cancer clinical trials. As data on toxicity, including nonclinical
and clinical toxicity, PK, and/or pharmacodynamics (PD) become available during drug
development, protocols should be revised to include patients with compromised organ function
where safe parameters regarding dosage adjustments have been determined.8
1. Renal function recommendations
• Eligibility criteria should be based on a contemporary, widely accepted, and
clinically applicable equation that estimates glomerular filtration rate or a
measure of glomerular filtration rate rather than an absolute serum creatinine
concentration. The equation used for a particular patient population should
remain consistent throughout the investigational drug development process.
• Sponsors should provide adequate justification for the inclusion/exclusion of
patients with various degrees of renal impairment based on the stage of
product development, safety profile of the product, understanding of the effect
of renal impairment on the elimination of the drug, and the safety of study
procedures in patients with renal impairment.
• Patients with renal impairment should be included in trials of investigational
drugs when the available nonclinical and clinical data indicate that inclusion
of patients with renal impairment would not place patients at unreasonable
risk and/or adequate steps can be taken to mitigate potential risks. When there
is an expectation that the systemic exposure will increase in patients with
renal dysfunction, inclusion of such patients may be facilitated by prospective
dose adjustment to produce similar systemic exposures to those seen in
patients with relatively preserved kidney function.9
8 Lichtman S, Harvey R, Smit M, et al., 2017, Modernizing Clinical Trial Eligibility Criteria: Recommendations of
the American Society of Clinical Oncology – Friends of Cancer Research Organ Dysfunction, Prior or Concurrent
Malignancy, and Comorbidities Working Group, JCO, 35(33): 3753-3759.
9 Public Workshop: Evaluating Inclusion and Exclusion Criteria in Clinical Trials, Workshop Report, July 2018,
workshop date April 16, 2018, available at https://www.fdanews.com/ext/resources/files/2018/08-22-18-
FDAsummary.pdf?1534970149 (accessed June 23, 2020).

Contains Nonbinding Recommendations
4
• Sponsors should address the need for and timing of studies to evaluate the
effect of dialysis on drug clearance and the need for dosage adjustment for
patients on dialysis.
If there is adequate representation of patients with varying degrees of renal impairment, as well
as data sufficient to adequately describe the impact of renal impairment on PK of the drug,
population pharmacokinetic (popPK) analyses of data from phase 2 or phase 3 clinical trials may
be sufficient to characterize the impact of renal function.
2. Cardiac function recommendations
• Inclusion of patients with cardiovascular dysfunction may be possible when
available nonclinical and clinical data, including PK and PD data, indicate that
inclusion of these patients does not expose them to unreasonable risk.
• Patients with significant clinical cardiac abnormalities (e.g., clinical heart
failure, unstable angina) should be excluded, especially in early-phase studies.
• Inclusion criteria should require investigator assessment of a potential
participant’s risk for heart failure with a validated clinical classification
system (e.g., the New York Heart Association Functional Classification).
• Ejection fraction (EF) measurement:
- EF measured by either echocardiography or multigated acquisition
scan is acceptable for determining cardiac EF for eligibility criteria
purposes.
• QTc Prolongation:10
- Sponsors should assess the effects of a drug on QTc during early
clinical development.
- Sponsors should determine whether a maximum QTc interval is
necessary as a clinical trial eligibility criterion based on whether there
is a specific known risk of QTc prolongation, either through non-
clinical (e.g., hERG) or clinical trial data.
10 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs (October 2005) and the ICH guidance for industry E14 Clinical Evaluation
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs – Questions and
Answers (R3) (June 2017) for additional information regarding QTc prolongation.

Contains Nonbinding Recommendations
5
3. Hepatic function recommendations
Unlike other organ systems, liver biochemical testing does not provide sufficient evidence of
adequate liver drug metabolic function. While estimates of hepatic function that incorporate
clinical variables as well as functional and laboratory values, such as the Child-Pugh and Model
for End-Stage Liver Disease scoring systems,11,12 are adopted as markers of hepatic metabolism
in dedicated PK studies, hepatic metabolism may also be influenced by cancer and inflammation,
even in the setting of normal scoring. To gauge hepatic drug transformation capacity, pre-
existing liver disease, as well as epidemiological, genetic, environmental, and historical variables
(e.g., chronic alcohol use and a past history of adverse drug reactions) should be ascertained.
Impaired hepatic blood flow, in particular when portal hypertension is evident, is critical to
assessing how the liver metabolizes drugs.
• Inclusion of patients with severe hepatic impairment should be discussed with
FDA.
• Patients with mild and moderate hepatic impairment13 (defined as the
equivalent of National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) grade 1 toxicity), as well as those with
aspartate transaminase (AST) and alanine transaminase (ALT) elevations
defined as grade 3 by the NCI CTCAE (> 5 to 20 x ULN (upper limit of
normal)), may be asymptomatic and able to tolerate doses equivalent to
patients with normal hepatic function.
• Inclusion of patients with mild to moderate hepatic impairment may be
appropriate when the available nonclinical and clinical data, including PK and
PD data, indicate that inclusion of these patients does not present an
unreasonable risk to patients.
B. Patients with prior or concurrent malignancy
Patients with prior malignancies of the same or different tumor type and patients with concurrent
malignancies of the same or different tumor type (referred to as prior or concurrent malignancies
in this guidance) whose natural history or treatment does not have the potential to interfere with
the safety or efficacy assessment of the investigational drug should generally be eligible for
enrollment in clinical trials. For example, in initial dose finding or preliminary activity-estimating
or proof-of-concept studies, patients with a history of prior or concurrent malignancies should not
be excluded.
11 See the guidance for industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data
Analysis, and Impact on Dosing and Labeling (May 2003).
12 See the Protocol Template for Organ Dysfunction Studies, updated February 5, 2020 for the NCI criteria,
available at https://ctep.cancer.gov/protocolDevelopment/templates_applications.htm (accessed June 23, 2020).
13 Talal AH, Venuto CS, Younis I, 2017, Assessment of hepatic impairment and implications for pharmacokinetics
of substance use treatment, Clin Pharmacol Drug Dev, 6: 206-212.