Severely Debilitating or Life-
Threatening Hematologic 
Disorders: Nonclinical 
Development of Pharmaceuticals 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2019 
Pharmacology/Toxicology 
 
   
Severely Debilitating or Life-
Threatening Hematologic 
Disorders: Nonclinical 
Development of Pharmaceuticals 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2019 
Pharmacology/Toxicology 
 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  NONCLINICAL EVALUATIONS ................................................................................. 3 
A.  Pharmacology ................................................................................................................................. 3 
B.  Safety Pharmacology ..................................................................................................................... 3 
C.  General Toxicology ........................................................................................................................ 3 
1. Studies to Support Change in Clinical Schedule ............................................................................. 4 
D.  Genotoxicity .................................................................................................................................... 4 
E.  Reproductive Toxicology ............................................................................................................... 5 
F.  Carcinogenicity .............................................................................................................................. 6 
G.  Immunotoxicity .............................................................................................................................. 6 
H.  Photosafety Testing ........................................................................................................................ 6 
I.  Pharmacokinetics ........................................................................................................................... 7 
IV.  TIMING OF NONCLINICAL STUDIES ...................................................................... 7 
V.  FIH DOSE AND DOSE ESCALATION......................................................................... 7 
VI.  OTHER STUDIES ............................................................................................................ 8 
A.  Combination of Pharmaceuticals ................................................................................................. 8 
B.  Nonclinical Studies to Support Studies in Pediatric Populations .............................................. 9 
  Contains Nonbinding Recommendations 
 
Severely Debilitating or Life-Threatening Hematologic Disorders: 
Nonclinical Development of Pharmaceuticals 
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 
 
The purpose of this guidance is to assist sponsors in the design of nonclinical studies for the 
development of pharmaceuticals used to treat patients with severely debilitating or life-
threatening hematologic disorders (SDLTHDs).2 This guidance is intended to streamline the 
development of pharmaceuticals used to treat patients with SDLTHDs, other than cancer, while 
still protecting patients safety and avoiding unnecessary use of animals, in accordance with the 
3R (reduce, refine, replace) principles. This guidance applies to pharmaceuticals used both to 
treat the active disease and to prevent the recurrence of a life-threatening or debilitating event. 
 
This guidance does not address radiopharmaceuticals, vaccines, cellular and gene therapy 
products, or blood products. This guidance provides recommendations for nonclinical studies in 
support of trials in patients only. For nonclinical studies in support of studies in healthy 
volunteers, consult the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (January 
2010).3 This guidance is not for anticancer pharmaceuticals intended to treat hematologic 
malignancies. For oncology indications, consult the ICH guidances for industry S9 Nonclinical 
Evaluation for Anticancer Pharmaceuticals (March 2010) and S9 Nonclinical Evaluation for 
Anticancer Pharmaceuticals Questions and Answers (June 2018). 
 
The draft guidances for industry titled Rare Diseases: Early Drug Development and the Role of 
Pre-IND Meetings (October 2018) and Rare Diseases: Common Issues in Drug Development 
(August 2015) do not specifically facilitate the nonclinical development of pharmaceuticals for 
                                                 
1 This guidance has been prepared by the Division of Hematology Oncology Toxicology in the Center for Drug 
Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, the term pharmaceuticals refers to small molecules, therapeutic proteins, 
antibodies, and related products, such as conjugated products that are regulated by CDER.   
 
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
  1  Contains Nonbinding Recommendations 
 
treatment of SDLTHDs. Because SDLTHDs are not all rare diseases, they can fall outside the 
scope of the draft guidances for rare diseases. The present document provides consistent 
guidance for all nononcology SDLTHDs, independent of disease incidence or prevalence. 
 
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 
 
SDLTHDs include conditions in which life expectancy is short or quality of life is greatly 
diminished despite available therapies. The Agency has defined life-threatening and severely 
debilitating diseases in regulations.4 Life threatening means diseases or conditions where the 
likelihood of death is high unless the course of the disease is interrupted and diseases or 
conditions with potentially fatal outcomes, where the endpoint of clinical trial analysis is 
survival.5 Severely debilitating means diseases or conditions that cause major irreversible 
morbidity.6 The following factors are examples that could be considered, alone or combined and 
in no specific order, to determine whether a hematologic disorder is severely debilitating or life-
threatening (SDLT): reduced life expectancy, organ damage or dysfunction, disability, need for 
hospitalization, risk of severe infection, or blood transfusion dependence. Other factors may be 
considered and should be discussed with the Agency. A hematologic disorder may be considered 
SDLT, despite available therapies, depending on how the patient population is defined (e.g., 
refractory), the effectiveness of available therapies, and whether available therapies include 
medications or procedures associated with undesired health outcomes (e.g., complications 
associated with organ transplant). 
 
Some examples of SDLTHDs are multicentric Castlemans disease; hemophagocytic 
lymphohistiocytosis; hypereosinophilic syndrome; amyloidosis; cold agglutinin; aplastic anemia; 
paroxysmal nocturnal hemoglobinuria; sickle cell disease; beta-thalassemia major; hemophilia; 
thrombotic thrombocytopenic purpura; and warts, hypogammaglobulinemia, immunodeficiency, 
and myelokathexis (WHIM) syndrome. The sponsor should discuss with the review division 
whether the indication is considered an SDLTHD.  
 
FDA supports the principles of the 3Rs, to reduce, refine, and replace animal use when 
appropriate. Although this guidance provides recommendations for nonclinical studies, sponsors 
can consult with the Agency if they wish to propose nonanimal testing methods or strategies not 
                                                 
4 See 21 CFR 312.81. 
 
5 21 CFR 312.81. 
 
6 21 CFR 312.81. 
 
  2  Contains Nonbinding Recommendations 
 
described in this guidance. The Agency will consider if such an alternative method or strategy 
could be used instead of an animal study.  
 
 
III.  NONCLINICAL EVALUATIONS 
 
A.  Pharmacology 
 
Before initiating clinical trials, the sponsor should conduct in vitro and/or in vivo proof-of-
concept studies to investigate the mode of action and effects of the pharmaceutical in relation to 
its intended therapeutic effect. Pharmacology studies can also provide information on species 
selection for toxicology studies, particularly for biotechnology-derived products. The sponsor 
should also evaluate potential secondary pharmacological characteristics of the pharmaceutical 
based on general screening approaches, as applicable. The sponsor should provide data from 
secondary pharmacology assessments, as applicable, with the initial investigational new drug 
(IND) application to assist in the safety evaluation. 
 
B.  Safety Pharmacology 
 
An assessment of the potential effect of the pharmaceutical on vital organ functions (including 
central nervous, cardiovascular, and respiratory systems) should be available before initiation of 
clinical trials. Detailed clinical observations following dosing and appropriate 
electrocardiographic measurements in nonrodents are generally considered sufficient. 
Conducting stand-alone safety pharmacology studies is not necessary. In cases where specific 
concerns have been identified that could put patients at significant additional risk, the sponsor 
should consider appropriate safety pharmacology studies described in the ICH guidances for 
industry S7A Safety Pharmacology Studies for Human Pharmaceuticals (July 2001) and S7B 
Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval 
Prolongation) by Human Pharmaceuticals (October 2005). In the absence of a specific risk, such 
studies will not be called for to support clinical trials or for marketing. 
 
C.  General Toxicology 
 
The sponsor should ensure that the planned dose of the pharmaceutical and the proposed safety-
monitoring plan for the initial clinical trials are supported by nonclinical data. In general, animal 
toxicology studies of 1 months duration are sufficient for initiation of first-in-human (FIH) trials 
and for continuous administration in patients beyond 1 month. Toxicology studies of shorter than 
1 months duration may be acceptable in support of clinical trials that are shorter than 1 month. 
In general, studies of 3 months duration are sufficient to support initiation of large-scale trials 
(e.g., phase 3) and marketing applications. When the investigational pharmaceutical extends 
survival or lessens the severity or the frequency of a debilitating event, toxicology studies of 6 to 
9 months duration are generally not warranted. The Agency still considers the results of 3-
month toxicology studies sufficient and that the data generated in patients are most meaningful 
and relevant to inform the safety of patients. 
 
  3  Contains Nonbinding Recommendations 
 
The sponsor should choose the design of nonclinical studies to accommodate different dosing 
schedules that might be utilized in initial clinical trials. It is not expected that the exact clinical 
schedule always will be followed in the toxicology study, but the information provided from the 
toxicity studies should be sufficient to support the clinical dose and schedule and to identify 
potential toxicity. For example, one factor the sponsor can consider is the half-life in the test 
species and the projected (or known) half-life in humans. Other factors could include exposure 
assessment, toxicity profile, saturation of receptors, etc. Identification of a no observed adverse 
effect level (NOAEL) in general toxicology studies is not always necessary; for example, when 
the initial clinical trial is in patients and the FIH dose may not be based on a NOAEL (see 
section V, FIH Dose and Dose Escalation). 
 
For small molecules, toxicology studies are generally conducted in two species (rodent and 
nonrodent). For biotechnology-derived pharmaceuticals, the principles of the ICH guidance for 
industry S6 (R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 
2011) apply in that a single pharmacologically relevant species may be acceptable for toxicology 
studies. Safety assessment in an animal model of the disease in lieu of (or in addition to) a 
toxicology study in healthy animals is acceptable when justified. The duration of studies 
conducted in an animal model of disease should be the same as those that would be done in 
healthy animals, unless a decrease in life span relating to the disease makes studies of standard 
duration not possible. Also, a study in an animal model of the disease could be of short duration 
when the toxicology data from an animal disease model would be significantly confounded by 
the disease state.  
 
For general toxicology studies used to support clinical development, the sponsor should provide 
a scientific assessment for the potential to recover from toxicity, but recovery groups do not need 
to be automatically included in all general toxicology studies. The sponsor can obtain this 
information by understanding that the particular effect observed is generally reversible or 
nonreversible or by including a recovery group in at least one study and one dose level, to be 
justified by the sponsor. 
 
   
1.  Studies to Support Change in Clinical Schedule 
 
When considering a change in the clinical schedule, the sponsor should conduct an evaluation of 
the existing clinical data to justify such change. If the clinical data alone are inadequate to 
support the change in schedule, the sponsor should consider results of toxicology studies 
previously conducted and any additional relevant factors (such as toxicities, half-life, duration of 
pharmacodynamic effects, receptor saturation) to determine the need for additional toxicity 
studies. In cases for which the available information does not support a change in clinical 
schedules, an additional toxicology study of up to 1 months duration in a single species is 
usually sufficient to support the new clinical schedule. 
 
D.  Genotoxicity 
 
The sponsor should provide an assessment of genotoxicity for small-molecule pharmaceuticals 
before initiating an FIH study; however, the complete battery is not always necessary. These 
  4  Contains Nonbinding Recommendations 
 
concepts are discussed in ICH M3(R2), ICH S9, and ICH S9 Questions and Answers guidance 
documents and further described below.  
 
An assay for gene mutation is generally sufficient to support single-dose clinical trials. To 
support multidose clinical trials, the sponsor should complete an additional assessment capable 
of detecting chromosomal damage in a mammalian system. The sponsor should also conduct a 
complete battery of tests for genotoxicity (as described in the ICH guidance for industry S2(R1) 
Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use 
(June 2012)) before initiating multidose phase 2 trials. The complete battery of genotoxicity 
studies is not necessary when there is clear indication of mutagenicity. For example, when the 
bacterial mutation (Ames) test is clearly positive, then additional genotoxicity testing is generally 
not warranted. When the bacterial mutation assay is negative, but an in vitro chromosome 
damage test result (such as chromosome aberration, micronucleus or mouse lymphoma tk+/ 
assay) is positive, the sponsor should consider in vivo genotoxicity testing.  
 
Genotoxicity studies are generally not called for with the initial IND when the investigational 
drug will be administered to patients only after available therapies that include genotoxic drugs. 
In such a case, the sponsor can submit results of genotoxicity studies with the marketing 
application.  
 
The sponsor of biopharmaceuticals should follow the principles outlined in the ICH guidances 
for industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 
(November 1997) and S6(R1) Addendum to Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals (May 2012). 
 
E.  Reproductive Toxicology 
 
The recommendations for reproductive toxicity evaluation for anticancer pharmaceuticals in the 
draft guidance for industry Oncology Pharmaceuticals: Reproductive Toxicity Testing and 
Labeling Recommendations (September 2017)7 (Oncology Pharmaceuticals draft guidance) are 
relevant for SDLTHDs and are described below. The Oncology Pharmaceuticals draft guidance 
takes into consideration recommendations in relevant guidance documents, such as those in ICH 
S9, the ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals 
Questions and Answers, and ICH S6 (R1). 
 
Embryo-fetal development (EFD) toxicity risk assessment of pharmaceuticals used to treat 
patients with SDLTHD should be available when the marketing application is submitted; the 
Agency does not consider these studies essential to support clinical trials. A weight-of-evidence 
approach showing potential for reproductive toxicity may eliminate the need to conduct a 
dedicated EFD study. The Oncology Pharmaceuticals draft guidance describes scenarios for 
which an EFD study is not warranted based on the patient population or the type of 
pharmaceuticals (e.g., use in postmenopausal women only or for drugs that are genotoxic and 
target rapidly dividing cells); these scenarios are applicable to SDLTHDs as well. 
 
                                                 
7 When final, this guidance will represent the FDAs current thinking on this topic. 
  5  Contains Nonbinding Recommendations 
 
Fertility and early embryonic development and pre- and postnatal development (PPND) studies 
are usually not warranted for treatment of patients with SDLTHD. In cases in which there is a 
well-understood high cure rate associated with the use of the investigational pharmaceutical or 
the investigational pharmaceutical results in substantial reduction in the occurrence of life-
threatening or debilitating events, fertility and PPND studies may be needed on a case-by-case 
basis. If the Agency considers these studies important, the results of such studies could be 
submitted after approval.   
 
The Oncology Pharmaceuticals draft guidance describes scenarios that are applicable to 
SDLTHDs and for which a fertility or PPND study is not warranted. For instance, a stand-alone 
fertility study is not warranted if, based on the totality of data (e.g., knowledge of the target 
biology and/or results of general toxicology studies), the sponsor identifies potential fertility risk 
or when the pharmaceutical will be used in postmenopausal women only. PPND studies are not 
needed for pharmaceuticals that cause malformations or result in high embryo-fetal death. 
 
F.  Carcinogenicity 
 
ICH S6(R1) and the ICH guidance for industry S1A The Need for Long-Term Rodent 
Carcinogenicity Studies of Pharmaceuticals (March 1996) address the need for a carcinogenicity 
study or assessment. Animal carcinogenicity studies, when warranted, can be deferred to after 
approval when the clinical development is short and carcinogenicity studies would delay product 
approval.8 
 
G.  Immunotoxicity 
 
For most pharmaceuticals used to treat patients with SDLTHDs, the Agency considers the design 
components of the general toxicology studies to be sufficient to evaluate immunotoxic potential 
in support of clinical trials and marketing. For pharmaceuticals activating the immune system, 
the sponsor should consider additional endpoints (such as immunophenotyping by flow 
cytometry) in the toxicology or proof-of-concept study design. 
 
H.  Photosafety Testing 
 
The sponsor should conduct an initial assessment of phototoxic potential before phase 1 based on 
photochemical properties of the pharmaceutical and information on other pharmaceuticals in the 
same class. If assessment of these data indicates a potential risk, the sponsor should take 
appropriate protective measures during outpatient trials. If the photosafety risk cannot be 
evaluated adequately with the use of nonclinical data or clinical experience, the sponsor should 
provide a photosafety assessment consistent with the principles described in ICH M3(R2) and 
the ICH guidance for industry S10 Photosafety Evaluation of Pharmaceuticals (January 2015) 
before marketing the pharmaceutical. 
 
                                                 
8 See the guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of 
the Federal Food, Drug, and Cosmetic Act (April 2011). 
 
  6  Contains Nonbinding Recommendations 
 
I.  Pharmacokinetics 
 
The evaluation of limited pharmacokinetic parameters (e.g., peak plasma/serum level, area under 
the curve (AUC), half-life) in the general toxicology studies can facilitate many aspects of a 
phase 1 clinical trial, such as dose selection, schedule of administration, and dose escalation. The 
sponsor should include pharmacokinetic endpoints in other toxicology studies as applicable, such 
as 3-month toxicology, reproductive toxicology, and carcinogenicity studies. Further information 
on absorption, distribution, metabolism, and excretion (ADME) of the drug in animals can 
normally be generated in parallel with clinical development when applicable. The ADME studies 
can be abbreviated for biological products (e.g., evaluation of metabolism is generally not 
warranted). 
 
 
IV.  TIMING OF NONCLINICAL STUDIES 
 
Table 1 indicates the recommended timing for submission of the results of nonclinical studies to 
the Agency, when applicable.   
 
Table 1. Timing for Submission of Nonclinical Studies* 
 
Nonclinical studies or assessments  Timing 
Pharmacology: primary  With initial IND; continuing through development 
Pharmacology: secondary  With initial IND 
Safety pharmacology  With initial IND 
Genetic toxicology  With initial IND; additional studies may be needed 
during drug development; the complete battery of 
studies not always necessary 
General toxicology study: 1 month  With initial IND 
General toxicology: 3 months  Before initiating a large-scale trial (e.g., phase 3) 
ADME  In parallel with clinical development  
Reproductive toxicology: EFD  With NDA/BLA 
Reproductive toxicology: fertility and  With NDA/BLA or after approval 
PPND (when needed) 
Carcinogenicity (when needed)  With NDA/BLA or after approval 
*IND = investigational new drug application; NDA = new drug application; BLA = biologics license application; 
ADME = absorption, distribution, metabolism, and excretion; EFD = embryo-fetal development; PPND = pre- and 
postnatal development. 
 
 
V.  FIH DOSE AND DOSE ESCALATION 
 
The goal of selecting the start dose is to identify a dose that is expected to have pharmacologic 
effects and is reasonably safe. The sponsor should scientifically justify the starting dose using all 
  7  Contains Nonbinding Recommendations 
 
available nonclinical data (e.g., pharmacokinetics, pharmacodynamics, toxicity). When the first-
in-human (FIH) study is conducted in patients, the FIH dose may be based on the severely toxic 
dose in 10% of rodents (STD ), the highest nonseverely toxic dose in nonrodents, the NOAEL 
10
in either species, or other approaches as relevant and justified. For most systemically 
administered small molecules, interspecies scaling of the animal doses to an equivalent human 
dose is usually based on normalization to body surface area. For both small molecules and 
biopharmaceuticals, interspecies scaling based on body weight, AUC, or other exposure 
parameters might be appropriate.  
 
For biopharmaceuticals with immune agonistic properties, the sponsor should consider selecting 
the start dose using a minimally anticipated biologic effect level. 
 
In general, the highest dose or exposure tested in the nonclinical studies does not limit the dose 
escalation or highest dose investigated in a clinical trial in patients with SDLTHD. When a steep 
dose- or exposure-response curve for severe toxicity is observed in nonclinical toxicology 
studies, or when no preceding marker of severe toxicity is available, smaller than usual dose 
increments (fractional increments rather than dose doubling) should be considered. 
 
 
VI.  OTHER STUDIES 
 
A.  Combination of Pharmaceuticals 
 
The sponsor should provide a rationale to support the combination, which can include in vitro or 
in vivo pharmacology data or a literature assessment. 
 
In general, toxicology studies investigating the safety of combinations of pharmaceuticals 
intended to treat patients with SDLTHDs are not warranted. Instead, pharmaceuticals planned for 
use in combination therapies should be well studied individually in toxicology studies. Well-
studied individually means a toxicological evaluation sufficient to support clinical studies of the 
individual pharmaceutical alone.  
 
If there is no or very limited human safety data for one of the combination components, the 
sponsor should consider a nonclinical pharmacology study of the combination, containing 
limited safety endpoints (such as mortality, clinical signs, and body weight). This would be in 
addition to the toxicology studies with the single agents. If sufficient clinical data (e.g., a 
completed phase 1 or a monotherapy phase within phase 1) are available with the individual 
pharmaceuticals, additional nonclinical studies may not be warranted. 
 
If there is no or very limited human safety data for one of the combination components, and yet 
the pharmaceutical is pharmacologically inactive in animal species, safety assessment of the 
combination can be based on relevant in vitro tests and/or mechanistic understanding of target 
biology. 
 
  8  Contains Nonbinding Recommendations 
 
If the available clinical and nonclinical data are insufficient to establish a safe starting dose of the 
combination, a dedicated toxicology study may be needed with the combination to establish a 
safe starting dose in humans. 
 
B.  Nonclinical Studies to Support Studies in Pediatric Populations 
 
Juvenile animal toxicology studies are not warranted to initiate clinical trials in pediatric 
populations for SDLTHDs when clinical data in adults are available. In this case, juvenile 
toxicology studies are not warranted concurrent with a pediatric study or to support product 
approval; data obtained in adult and pediatric patients will be more relevant for safety assessment 
and labeling. On a case-by-case basis, juvenile toxicology studies may be warranted to address 
specific targeted questions that could not be answered through the adult or pediatric clinical 
study or existing nonclinical data.  
  9