Cancer Clinical Trial 
Eligibility Criteria:  
Patients with HIV, 
Hepatitis B Virus, or 
Hepatitis C Virus 
Infections  
 
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 HIV, Hepatitis 
B Virus, or Hepatitis C 
Virus Infections  
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.  Recommendations for patients with HIV infection .................................................................... 3 
1. Evaluation of immune function ........................................................................................................ 3 
2. HIV therapy ...................................................................................................................................... 4 
B.  Recommendations for patients with evidence of chronic HBV infection or patients with   
history of chronic HCV or virologically suppressed on HCV treatment ................................... 5 
1. Liver-related laboratories ................................................................................................................ 5 
2. HBV/HCV therapy ........................................................................................................................... 6 
APPENDIX 1: REFERENCES FOR MANAGEMENT OF CONCURRENT HIV AND 
HEPATITIS B ............................................................................................................................... 7 
APPENDIX 2: REFERENCES FOR AVAILABLE ANTIRETROVIRAL, HEPATITIS B, 
AND HEPATITIS C DRUGS AND RELEVANT PHARMACOLOGY TO AVOID DRUG-
DRUG INTERACTIONS ............................................................................................................. 8 
 
 
 
   
 
  Contains Nonbinding Recommendations 
 
Cancer Clinical Trial Eligibility Criteria:  
Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus 
Infections  
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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), and 
hepatitis C virus (HCV) infections. This guidance is intended to assist stakeholders, including 
sponsors and institutional review boards, responsible for the development and oversight of 
clinical trials.  
 
A clinical trials 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 brain metastases, for patients 
with organ dysfunction or prior or current malignancies, and regarding minimum age considerations for inclusion of 
pediatric patients. 
 
  1  Contains Nonbinding Recommendations 
 
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 therapys 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 elsewhere 6,7 and are not addressed in this guidance 
because the considerations are not specific to enrolling patients with HIV, HBV, or HCV 
infections. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 
 
HIV and HBV infections can be chronically managed and HCV infections can be cured with 
contemporary antiviral therapy. These viral infections may increase the risk of development of 
several malignancies. However, exclusion of patients with HIV, HBV, or HCV infections from 
cancer clinical trials remains common in most studies of investigational drugs. Expanding cancer 
clinical trial eligibility to be more inclusive of patients with HIV, HBV, or HCV infections is 
justified in many cases, and may accelerate the development of effective therapies in cancer 
patients with these chronic infections. Designing cancer clinical trials that include patients with 
HIV, HBV, or HCV infections 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 FDAs 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. 
 
  2  Contains Nonbinding Recommendations 
 
III.  RECOMMENDATIONS     
 
Thoughtful consideration should be given to the potential inclusion of patients infected with 
HIV, HBV, or HCV in cancer clinical trials. Eligibility criteria that address requirements 
regarding relevant concurrent antiviral and other therapies (e.g., antibiotic prophylaxis) and 
degree of immunocompetence in patients with HIV, HBV, or HCV infections should be designed 
in a manner that is appropriate for a given cancer, investigational drug (for instance taking into 
account immunosuppressive potential), and intended use population.8 In cases where there is a 
strong rationale for exclusion, the rationale should be addressed in the trial protocol. 
 
The following recommendations for eligibility criteria for patients with cancer and concurrent 
HIV infection are focused on evaluation of immune function and HIV therapy. The following 
recommendations for eligibility criteria for patients with cancer who have evidence of chronic 
HBV or with history of chronic HCV or virologically suppressed on HCV treatment are focused 
on liver-related laboratories and HBV/HCV therapy.  
 
A.  Recommendations for patients with HIV infection 
 
1.  Evaluation of immune function  
 
  Eligibility based on CD4+ T-cell counts 
 
-  Patients with CD4+ T-cell (CD4+) counts  350 cells/uL should 
generally be eligible for any study. 
 
-  Patients with a lower CD4+ count (< 350 cells/uL) should generally be 
eligible if the patient has a potentially curable malignancy or for 
interventions in a later stage of development that have demonstrated 
prior activity with a given cancer. 
 
  Eligibility based on history of AIDS (acquired immunodeficiency 
syndrome)-defining opportunistic infections 
 
-  Patients without a history of AIDS-defining opportunistic infections 
should generally be eligible for any study. 
 
-  Patients with a history of AIDS-defining opportunistic infections may 
be eligible, taking into account the time frame and cancer type: 
 
o  In general, patients should be eligible if they have not had an 
opportunistic infection within the past 12 months. 
 
                                                 
8 Uldrick T, Ison G, Rudek M, et al., 2017, Modernizing Clinical Trial Eligibility Criteria: Recommendations of the 
American Society of Clinical OncologyFriends of Cancer Research HIV Working Group, JCO, 35(33): 3774
3780. 
  3  Contains Nonbinding Recommendations 
 
o  For studies of patients with a history of AIDS-defining cancers 
(e.g., Kaposis sarcoma, aggressive B-cell lymphoma, and 
invasive cervical cancer) with curative potential, exclusion of 
patients with uncontrolled opportunistic infections may be 
appropriate. 
 
o  Patients on prophylactic antimicrobials should be included, 
although patients taking specific antimicrobial drugs where 
there may be drug-drug interactions or overlapping toxicities 
should if appropriate, be changed to an alternative 
antimicrobial, or if not, be excluded. 
 
2.  HIV therapy9  
 
  Timing of antiretroviral therapy (ART) initiation  Eligibility criteria 
specifying timing of initiation of ART should be based on study goals and 
take into consideration patients recently diagnosed with HIV or patients not 
on effective ART. Effective ART is defined as a drug, dosage, and schedule 
associated with reduction and control of the viral load. 
 
-  For advanced cancer settings in which there is not curative intent: 
To ensure that effective ART is tolerated and that toxicities are not 
confused with investigational drug toxicities, trial participants should 
be on established ART for at least four weeks and have an HIV viral 
load less than 400 copies/mL prior to enrollment.  
 
-  For therapies given in a potentially curative setting: Participants 
should agree to adhere to ART based on protocol defined treatment 
guidelines taking into account any evidence for multidrug resistance. 
 
  Exclusion of specific ART drugs  It may be necessary or appropriate to 
exclude patients taking certain ART drugs based on demonstrated or predicted 
drug-drug interactions that affect absorption, distribution, metabolism, and 
excretion of the investigational drug (or the ART) or for potential overlapping 
toxicities. 
 
-  Drug-drug interactions with ART occur via many mechanisms, with 
cytochrome P450 3A4 (CYP3A4)-mediated interactions being the 
most common. The absorption, distribution, metabolism, and excretion 
data known to date for the investigational drug should be assessed. 
Exclusion of patients on specific ART drugs should then be based on 
the potential for clinically significant drug-drug interactions using 
known information (see Appendix 2). The protocol should include 
tables of any drugs, including ART and other drugs, that are prohibited 
                                                 
9 See Appendix 1 for references regarding management of concurrent HIV infection. 
  4  Contains Nonbinding Recommendations 
 
for patients while participating in the study, and therefore would be 
considered part of the exclusion criteria for the study. For sensitive 
CYP3A4 substrates, patients who are using concurrent strong 
CYP3A4 inhibitors (e.g., ritonavir, cobicistat) or strong CYP3A4 
inducers could be switched to an alternate effective ART regimen 
(with minimal drug-drug interaction potential) before study 
participation or should be excluded from the study if their regimen 
cannot be altered. Otherwise eligible study participants could be 
switched to an alternate effective ART regimen before study 
participation. 
 
-  Consider exclusion of patients on specific ART drugs based on 
toxicity (e.g., tenofovir (renal dysfunction), atazanavir (PR 
prolongation and AV block), efavirenz (depressed mood)) if 
overlapping toxicities with investigational drugs are expected and it is 
not possible to switch to an alternative effective ART regimen during 
treatment with the investigational drug. 
 
  Exceptions to concurrent ART  Although effective ART is recommended 
in patients with HIV infection, exceptions to concurrent ART could be 
considered in both development of eligibility criteria and conduct of studies, 
as follows:10  
 
-  In studies enrolling patients with curable malignancies where cancer 
therapy requires prioritization, eligibility criteria should permit 
enrollment, since treatment interruption or deferred initiation of ART 
is appropriate in curable malignancies when ART may compromise 
intended full-dose cancer therapy with investigational drug(s). 
 
-  For treatment interruptions for toxicity management. 
 
-  For treatment interruptions to meet scientific objectives of the study. 
 
B.  Recommendations for patients with evidence of chronic HBV infection or 
patients with history of chronic HCV or virologically suppressed on HCV 
treatment  
 
1.  Liver-related laboratories 
 
  Liver-related laboratory eligibility criteria should generally be the same as that 
for the general population. 
 
-  Exception: AST/ALT and bilirubin criteria may be less stringent in 
patients with cancers such as hepatocellular carcinoma and 
                                                 
10 Uldrick T and Little R, 2015, How I Treat Classical Hodgkin Lymphoma in Patients Infected with Human 
Immunodeficiency Virus, Blood, 125(8):1226-1235. 
  5  Contains Nonbinding Recommendations 
 
cholangiocarcinoma in whom hepatic function based on Child-Pugh 
score should be used. 
 
2.  HBV/HCV therapy 
 
  HBV: HBV reactivation can occur in chronic carriers of HBV infection 
(HBsAg-positive, undetectable or low HBV DNA, and normal ALT) who are 
not on HBV therapy, or in individuals who have serologic evidence of a 
resolved prior HBV infection (i.e., HBsAg-negative and anti-HBcpositive). 
While HBsAg-negative, anti-HBcpositive patients are at lower risk of HBV 
reactivation compared with HBsAg-positive patients, risk of HBV reactivation 
should be considered in all patients and the need for anti-HBV prophylaxis 
should be carefully assessed prior to the initiation of anticancer therapy.11 
Eligibility criteria for patients with chronic HBV infection with active disease 
who meet the criteria for anti HBV therapy should require the patient be on a 
suppressive antiviral therapy prior to initiation of cancer therapy.12  
 
  HCV: Eligibility criteria for patients with a history of HCV infection should 
generally require patients to have completed curative antiviral treatment and 
require HCV viral load below the limit of quantification. A patient who is 
HCV Ab positive but HCV RNA negative due to prior treatment or natural 
resolution should be eligible. For incurable cancers, patients with untreated 
HCV may be enrolled if the HCV is stable, the patient is not at risk for hepatic 
decompensation, and the investigational cancer treatment is not expected to 
exacerbate the HCV infection.  
 
  HCV: Eligibility criteria for patients on concurrent HCV treatment should 
generally require patients to have HCV below the limit of quantification. 
   
                                                 
11 Terrault NA, Lok AS, McMahon BJ, et al., 2018, Update on Prevention, Diagnosis, and Treatment of Chronic 
Hepatitis B: AASLD 2018 Hepatitis B Guidance, Hepatology, 67(4): 1560-1599. 
12 Reddy K, Beavers K, Hammond S, et al., 2015, American Gastroenterological Association Institute Guideline on 
the Prevention and Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug Therapy, 
Gastroenterology, 148(1): 215-219. 
  6  Contains Nonbinding Recommendations 
 
APPENDIX 1: REFERENCES FOR MANAGEMENT OF CONCURRENT HIV AND 
HEPATITIS B 
 
 
1.  HIV - Department of Health and Human Services (HHS) Guidelines for the Use of 
Antiretroviral Agents in Adults and Adolescents with HIV13 
 
2.  HIV - HHS Guidelines for the Prevention and Treatment of Opportunistic Infections in 
Adults and Adolescents with HIV14 
 
3.  HBV  Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 
2018 Hepatitis B Guidance15 
 
   
                                                 
13 Available at https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0, accessed June 
23, 2020. 
14 Available at https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf, accessed June 23, 2020. 
15 Terrault NA, Lok ASF, McMahon BJ, et al., 2018, Hepatology, 67(4): 1560-1599.  
  7  Contains Nonbinding Recommendations 
 
APPENDIX 2: REFERENCES FOR AVAILABLE ANTIRETROVIRAL, HEPATITIS B, 
AND HEPATITIS C DRUGS AND RELEVANT PHARMACOLOGY TO AVOID DRUG-
DRUG INTERACTIONS 
 
 
1.  HIV - Literature16,17 
 
2.  HIV - University of Liverpool HIV Drug Interaction Website Searchable Database18 
 
3.  HIV - FDAs Website  HIV Treatment Information for Adults19 
 
4.  HBV and HCV - University of Liverpool HEP Drug Interaction Website Searchable 
Database20 
 
5.  HCV  HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis 
C21 
 
                                                 
16 Rudek M, Flexner C, Ambinder R, 2011, Use of Antineoplastic Agents in Patients with Cancer Who Have 
HIV/AIDS, Lancet Oncol, 12(9): 905-912. The article includes tables on drug interaction potential of antiretroviral 
drugs. 
17 Berretta M, Caraglia M, Martellotta F, et. al., 2016, Drug-Drug Interactions Based on Pharmacogenetic Profile 
between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection, 
Front. Pharmacol., epub March 30, 2016, doi: 10.3389/fphar.2016.00071. 
18 Available at https://www.hiv-druginteractions.org/, accessed June 23, 2020.   
19 Available at https://www.fda.gov/drugs/hiv-treatment/hiv-treatment-information-adults, accessed June 23, 2020. 
20 Available at https://www.hep-druginteractions.org/, accessed June 23, 2020. 
21 Available at https://www.hcvguidelines.org/evaluate/monitoring, accessed June 23, 2020. 
  8