S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals 
Questions and Answers 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2018 
ICH 
 
   
S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals 
Questions and Answers 
Guidance for Industry 
 
Additional copies are available from: 
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Food and Drug Administration 
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and/or 
 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2018 
ICH 
 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION  SCOPE (1)  ............................................................................... 1 
II.  STUDIES TO SUPPORT NONCLINICAL EVALUATION (2) ............................... 3 
III.  NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND 
MARKETING (3)....................................................................................................... 6 
IV.  OTHER CONSIDERATIONS (4) .............................................................................. 8 
V.  ANNEX: QUESTIONS AND ANSWERS LINKED TO THE RESPECTIVE 
SECTIONS OF ICH S9 GUIDANCE (5) ................................................................. 11 
 
  Contains Nonbinding Recommendations 
 
S9 Nonclinical  Evaluation for Anticancer Pharmaceuticals 
Questions and Answers 
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.   
 
 
Since the ICH guidance S9 Nonclinical Evaluation for Anticancer Pharmaceuticals was 
finalized  (ICH S9 or ICH S9 guidance),2  all parties using the guidance have experienced 
some challenges with implementation  of the recommendations  on nonclinical  evaluation for 
anticancer pharmaceuticals.  This question-and-answer guidance is intended to facilitate the 
implementation  of ICH S9,  as well as to continue progress in the 3Rs of Reduction, 
Refinement, and Replacement in the use of animals. 
 
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.  
 
 
I.  INTRODUCTION  SCOPE (1)3 
 
Q1.  The ICH S9 guidance provides information for pharmaceuticals that are intended to 
treat cancer in patients with serious and life-threatening malignancies.  Are all 
initial development plans for anticancer pharmaceuticals covered under ICH S9 
guidance? (1.1) 
 
                                              
1 This guidance was developed within the Implementation Working Group of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), and 
has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document was 
endorsed by the ICH Assembly at Step 2a of the ICH process, June 2016.  At Step 2b of the process, the final draft is 
recommended for adoption to the regulatory bodies of the ICH regions. 
2 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs or Biologics guidance web pages at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInvormation/Guidances/default.htm.  
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
3 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Assembly at Step 2a of 
the ICH process, June 2016.   
  1  Contains Nonbinding Recommendations 
 
As most initial  development programs are performed in patients (adult and pediatric) whose 
disease is resistant and refractory to available therapy, the nonclinical  program described in ICH 
S9 is applicable.  See also the answer to Question 2 (1.2).  For other initial  development 
programs in cancer that is not resistant and refractory,  ICH S9 should be used as a starting point, and 
other studies added as appropriate with reference to ICH M3(R2) and S6(R1).  In some situations 
where the development  pathway is not clear, regulatory agencies should be consulted. See also 
the answer to Question 5 (1.5). 
 
Q2.  If the first in human (FIH) study is conducted in a patient population with resistant 
and refractory disease, will subsequent Phase I studies in a different cancer, but still 
a resistant and refractory population, still be covered under ICH S9? (1.2) 
 
Yes. 
 
Q3.  In general, the guidance has been interpreted as applying when the patients life 
expectancy is approximately 3 years.  It would be useful to provide further clarity 
about the intended population. (1.3) 
 
The ICH S9 guidance does not make a reference to years of life expectancy and the application 
of the guidance should  not be based on an expectation of survival  as measured in years.  The 
intent of the scope is clarified in Questions 1 (1.1) and 2 (1.2). 
 
Q4.  Can the principles of ICH S9 be applied to non-oncology therapeutics where the 
disease is life-threatening with limited therapeutic options? (1.4) 
 
These indications  are outside of the scope of ICH S9.  See ICH M3(R2) for guidance on when 
particular studies can be abbreviated, deferred, omitted, or added on a case-by-case approach to 
optimize  drug development for life-threatening  or serious diseases other than cancer. 
 
Q5.  Are clinical trials in the adjuvant or neo-adjuvant setting covered under ICH S9? 
(1.5) 
 
Yes. ICH S9 should be used as the starting point for drugs used in an adjuvant or neo-adjuvant 
setting even when there is a lack of detectable residual disease.  Data generated in patients (e.g., 
when the initial  program was in a refractory late stage disease) should be considered and may 
be used to abbreviate the nonclinical  program.  In cases in which there is a well understood 
high cure rate and a low and/or long delayed disease recurrence rate, then further studies (e.g., 
carcinogenicity,  a complete program on reproductive and developmental  toxicity)  are likely  to 
be needed prior to marketing.  In cases in which these factors are less defined and recurrence is 
high or rapid then the need for additional  studies and their timing  can be addressed on a case-
by-case basis, taking into account the totality of preclinical  and clinical  safety data, cure rate 
and expected time to recurrence. 
 
If the initial  development  program  is in the adjuvant  or neo-adjuvant  setting,  additional 
nonclinical  studies  may be needed,  including  longer-term  general toxicology  studies. 
 
  2  Contains Nonbinding Recommendations 
 
In all cases, it is important to consider the natural course of the disease.  The application  of 
ICH S9 and any omission  of studies should be justified  by the sponsor.  See also the response to 
Questions 1 (1.1), 6 (1.6), and 7 (1.7). 
 
Q6.  In the case where a therapeutic increases survival, what further toxicology work is 
recommended, and what is the appropriate  timing of any studies? (1.6) 
 
When the anticancer pharmaceutical  is shown to extend survival  of patients,  no additional 
general toxicology  studies  are usually  warranted.  The clinical  safety data in the intended 
population  is more relevant to assess human risks than those generated in additional  animal 
studies.  Additional  toxicology  studies other than general toxicology may be 
needed on a case-by-case basis.  If additional  studies are deemed important,  such studies could 
be submitted post approval of the anticancer pharmaceutical.  See also the answer to Question 7 
(1.7). 
 
Q7.  The scope indicates that in patients with long expected survival, the 
recommendations for additional nonclinical general toxicology studies depend on 
the available nonclinical and clinical data and the nature of toxicities observed.  Are 
additional nonclinical safety tests needed, when an anti-cancer pharmaceutical, in 
clinical development or approved for a particular malignant tumor according to the 
ICH S9 guidance, is to be applied to another oncology indication that is not 
immediately life-threatening, but is serious? (1.7) 
 
When moving  therapeutic development  from an approved indication  in oncology  or from an 
unapproved indication  with a sufficient nonclinical  and clinical  safety dataset, to an unapproved 
oncology  indication  that is not immediately  life-threatening  but is serious, additional  general 
toxicology  studies, e.g., chronic studies (6- or 9-month-studies)  are generally not warranted.  
Similar  to the response under Question 6 (1.6) the clinical  safety data generated in the patient 
population  for the approved indication  are most meaningful  and relevant to inform the safety 
plan for the patient population  in  the  unapproved  indication.   Toxicology  studies  other  than 
general  toxicology  may  be needed on a case-by-case basis. 
 
 
II.  STUDIES TO SUPPORT NONCLINICAL EVALUATION (2) 
 
Q8.  In Section 2.1 Pharmacology, the guidance states that studies should characterize 
the anti-tumor activity of the pharmaceutical.  The inference is that these are in 
vivo studies.  Is in vivo characterization necessary to address pharmacology? (2.1) 
 
If in vitro systems that are used for pharmacology  studies of anti-tumor  activity  are 
demonstrated to generate relevant data, then they should be considered sufficient. 
 
Q9.  Should recovery groups be included in toxicology studies supporting FIH toxicology 
studies? (2.2) 
 
  3  Contains Nonbinding Recommendations 
 
A scientific assessment of the potential to recover should be provided in all general toxicology 
studies used to support clinical  development although  recovery groups should not automatically 
be included  in all general toxicology  studies.  This information  can be obtained by an 
understanding  that the particular effect observed is generally reversible or  non-reversible or by 
including  a recovery period in at least one study and one dose level, to be justified  by the 
sponsor. 
 
Q10.  Should recovery groups be included on 3-month toxicology studies to support Phase 
III? (2.3) 
 
Recovery in 3-month studies is not specifically warranted unless there is a concern from short-
term toxicology  or from clinical studies that recovery animals could address: for example, when 
a recovery group was not included in the short-term toxicology  study and there was insufficient 
understanding whether a particular effect observed may be reversible or non-reversible.  Another 
example is when the 3-month studies are undertaken in the absence of clinical data or with 
limited  clinical data. 
 
A scientific  assessment of the potential  to recover from toxicity  should be provided  for general 
toxicology  studies used to support clinical  development, although recovery groups should not 
automatically  be included  in all general toxicology  studies. A more directed approach using 
appropriate models can be appropriate to address a specific safety question. 
 
Q11.  Patients with cancer are often given supportive care drugs (e.g., antibiotics).  Is 
there a situation where adding supportive care drugs to toxicology studies are 
appropriate? (2.4) 
 
Treating affected animals with supportive care during toxicology  studies can be appropriate in 
some cases, e.g., when secondary infection  due to immunosuppression  is observed on the 
study.  Giving  supportive care prophylactically  to all animals is generally not recommended. 
 
Q12.  Is there any guidance on the need for abuse liability studies for drugs developed 
under ICH S9? (2.5) 
 
Nonclinical  studies for abuse liability  are generally  not warranted to support clinical  trials or 
marketing of pharmaceuticals for the treatment of patients with advanced cancer. 
 
Q13.  What is the utility of tissue cross reactivity studies for biopharmaceuticals 
containing a complementary determining region (CDR) (i.e., monoclonal antibodies 
(mAbs), antibody drug conjugates (ADCs)) that fall under ICH S9, and do these 
studies need to be conducted? (2.6) 
 
In general,  tissue cross reactivity studies have little utility and are not needed with the initial  first-
in-human study or later in development,  unless there is a specific cause for concern.  In cases 
where there are no pharmacologically  relevant species, human tissue cross reactivity or 
alternative methods should be considered for the first-in-human study. 
 
  4  Contains Nonbinding Recommendations 
 
Q14.  The guidance allows for testing in only one species if there is a positive signal for 
embryofetal lethality or teratogenicity.  If clear evidence of embryofetal lethality or 
teratogenicity is observed in a dose-range finding study in one species, is a definitive 
study in that species recommended? (2.7) 
 
A definitive study is generally not warranted if a dose-range finding  study (including non-good 
laboratory practice (GLP)) shows clear evidence of embryofetal lethality  or teratogenicity.  This 
dose-ranging study in a single species would be sufficient to support marketing. 
 
Q15.  Section 2.5 describes the use of alternative assessments for biopharmaceuticals.  Is 
there any role of alternative in vitro and in vivo assays for small molecules in 
reproductive toxicology assessment? (2.8) 
 
Yes.  Alternative assessments may be used to aid in the safety assessment for reproductive risk. 
 
Q16.  When the only relevant species is a non-human primate (NHP) and the mechanism 
of action is expected to yield a reproductive toxicity risk and/or knock out animals 
or use of surrogate biologics in  rodents have demonstrated a reproductive risk, 
should these approaches be considered sufficient for hazard identification, or should 
a study in pregnant NHPs be conducted? (2.9) 
 
A weight-of-evidence  assessment of reproductive  risk should be provided. An NHP study to 
assess a hazard to embryofetal development (EFD) should not be considered a default approach.  
If the weight-of-evidence clearly indicates a risk, an EFD study in NHP is not warranted.  
Development toxicity  studies in  NHPs can only  provide  hazard identification  according  to 
ICH S6 (R1).  The expected reproductive hazard should be appropriately indicated on the label. 
 
Q17.  Is there a need for nonclinical lactation and placental transfer studies? (2.10) 
 
There is no specific need for lactation or placental transfer studies. 
 
Q18.  Which and how many in vitro genotoxicity studies would need to be positive in 
order to make the in vivo genotoxicity assays unwarranted (Section 2.6 
Genotoxicity)? (2.11) 
 
When the bacterial mutation (Ames) test is positive,  then in vivo genotoxicity  testing is 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,  in vivo genotoxicity  testing should be considered. Refer to ICH S2(R1) for additional 
information. 
 
Q19.  Section 2.9 Photosafety Testing states that if initial assessment of phototoxic 
potential based on physicochemical properties indicates a phototoxic risk, when 
should nonclinical photosafety studies be conducted? (2.12) 
 
  5  Contains Nonbinding Recommendations 
 
ICH S9 should be consulted for the timing of phototoxicity  studies.  ICH S10 should be consulted 
for assessment of photosafety. 
 
 
III.  NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND 
MARKETING (3) 
 
Q20.  In section 3.1 Start Dose of First Administration in Humans reference is made to 
immune agonist biopharmaceuticals.  Small molecule drugs can also be immune 
agonists.  Can a minimally anticipated biological effect level (MABEL) approach 
also be used for small molecules? (3.1) 
 
If appropriate,  a MABEL could be used for small molecules using in vivo or in vitro data.  This 
approach should be considered if risk factors are derived from knowledge of (1) the mode of 
action, (2) the nature of the target, and/or (3) the relevance of animal or in vitro models. 
 
Q21.  Is use of the highest non-severely toxic dose ((HNSTD), Note 2) to select an 
appropriate starting dose applicable to biopharmaceuticals? (3.2) 
 
The HNSTD may be appropriate in determining  a starting dose of a biopharmaceutical (e.g., 
when a drug is not an immune agonist) taking into  consideration  differences in binding  affinity 
between animals and humans and pharmacological  properties of the biopharmaceutical 
(including  ADCs). 
 
Q22.  ICH S9 states that in cases where the available toxicology information does not 
support a change in clinical schedules, an additional toxicology study in a single 
species is usually sufficient.  What additional toxicology studies should be 
conducted, i.e., a 1-month or 3-month toxicology study, if the 3-month studies with 
the original schedule have already been conducted? (3.3) 
 
If needed,  a study  of up  to 1 month  duration  should  generally  be sufficient  to support a 
change in schedule and to support marketing (see ICH S9, Table 1 for additional  guidance).  This 
study should be available prior to the initiation  of the clinical  trial. 
 
Q23.  What general toxicology studies are recommended for continued clinical 
development, including marketing, for genotoxic drugs targeting rapidly dividing 
cells? (3.4) 
 
For genotoxic  drugs targeting  rapidly  dividing  cells (e.g., nucleoside  analogs,  alkylating 
agents, microtubule  inhibitors)  that have anti-proliferative  effects (evident in rapidly growing 
tissues) and are expected to be consistent across different species, toxicity  studies in one rodent 
species of 3-month duration are considered sufficient for continued clinical  development and 
registration. 
 
Q24.  Section 3.5 of ICH S9 states that pharmaceuticals planned for use in combination 
should be well studied individually in toxicology evaluations. How are these 
  6  Contains Nonbinding Recommendations 
 
nonclinical data considered well studied individually in toxicology evaluations to 
support a combination study?  If needed, when would a dedicated toxicology study 
be recommended? (3.5) 
 
Well-studied  individually  means a toxicological  evaluation  sufficient to support clinical 
studies of the individual  pharmaceutical alone.  If sufficient clinical  data (e.g., a completed 
Phase I or a monotherapy  phase within  Phase I) are available  with the individual 
pharmaceuticals, additional  nonclinical  toxicology  data may not be warranted.  A 
rationale to support the combination  should  be provided,  which can include in vitro or in vivo 
pharmacology  data or a literature assessment. 
 
If there are no or very limited  human safety data for one of the combination  components, a 
nonclinical  pharmacology  study of the combination  should  be considered,  in addition  to the 
toxicology  studies with the single agents. 
 
For pharmaceuticals that are pharmacologically  inactive in animal  species, assessment of 
combination  can be based on relevant in vitro tests and/or a mechanistic understanding of target 
biology. 
 
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. 
 
Q25.  Section 3.5 of ICH S9 states that data to support a rationale for the combination 
should be provided prior to starting the clinical study.  What are data to support a 
rationale for the combination study? (3.6) 
 
A scientific  rationale  should  be provided  to justify  a combination  clinical  study.  Data 
demonstrating  increased anti-tumor activity by combined pharmaceuticals in pharmacology 
studies  (e.g., animal  tumor  models,  in  vitro  or in  vivo  studies  based on mechanistic 
understanding  of target biology)  should  be provided  to support rationale for the combination, 
if feasible.  This  data could  be from in-house  studies or the scientific literature. 
 
Q26. Does the ICH S9 guidance apply to the drug itself having no anti-tumor activity, such 
as an enhancer, that is intended to be developed as the pharmaceutical combined 
only with the certain anti-tumor pharmaceutical for the treatment of patients with 
advanced disease in late stage development?  If ICH S9 does apply, which 
nonclinical studies are recommended for a first in human, clinical development and 
marketing application?  (3.7) 
 
Yes, these pharmaceuticals are within the scope of ICH S9 if they are intended to treat cancer.  
Data to show that the enhancer is non-active  should  be provided. General toxicology,  safety 
pharmacology,  and reproductive toxicology  assessments should be done for the combination.   
The enhancer alone may have a more limited  safety assessment either as an arm in the general 
toxicology  combination  study or as a stand-alone general toxicology  study of up to 1 month 
duration (see Table 1 in ICH S9).  Genotoxicity  studies may be conducted with each 
  7  Contains Nonbinding Recommendations 
 
pharmaceutical alone or with the combination,  as relevant.  The timing  of the studies should 
follow ICH S9. 
 
 
IV.  OTHER CONSIDERATIONS (4) 
 
Q27.  Section 4.1 of the guidance states that the safety of the conjugated material is the 
primary concern, and the safety of the unconjugated material can have a more 
limited evaluation. For an ADC, what does a more limited evaluation mean? (4.1) 
 
The unconjugated  material in Section 4.1 of ICH S9 refers to the payload.   
 
The whole ADC molecule  should  be tested in  at least one species.  See Question  29 (4.3) 
for a discussion  of the payload. 
 
Q28.  If the antibody of an ADC has not been separately characterized, should an arm of 
the antibody only be included in a toxicology study? (4.2) 
 
In general, studies of the mAb alone are not warranted. 
 
Q29.  Are studies with the payload and/or linker only recommended? (4.3) 
 
The pilot  studies and the nature of the payload will  determine what additional  studies, if any, 
are appropriate with the payload or payload with linker.  Evaluation  of the linker alone is not 
usually warranted.  If the toxicity  of the payload or payload with linker has been characterized 
(e.g., through  pilot  studies),  a GLP study of the payload or payload with linker may not be 
warranted or could be further abbreviated.  If the toxicity  of the payload or payload with linker 
has not been characterized, the payload or payload with linker could be evaluated in one species 
as a stand-alone study or could be added as an arm into toxicology  studies of the ADC.  See also 
note 2 of ICH S6 (R1). 
 
Q30.  What toxicokinetic (TK) analysis should be performed?  Should the free antibody 
and  free payload be distinguished from the ADC? (4.4) 
 
Current best TK practices for ADCs are to measure the level of ADC and the payload, and an 
estimate of the amount of free antibody should be provided. 
 
Q31.  Should plasma stability be included as part of the FIH study plan?  If not, at what 
stage of development is it needed? (4.5) 
 
In vitro data about plasma stability  of ADC in human and toxicology  species should  be 
available to support FIH trials. 
 
Q32.  Is there a recommended approach to setting an FIH starting dose for an ADC? (4.6) 
 
  8  Contains Nonbinding Recommendations 
 
A starting dose for use in cancer patients should be consistent with ICH S9. For example, for 
cytotoxic payloads, the starting clinical  dose can be determined using either 1/10th the Severely 
Toxic Dose (STD) in 10 percent of animals (STD10) in rodents or 1/6th the Highest Non- 
Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, 
depending on which is the most appropriate and/or sensitive species.  Other approaches can be 
considered for new classes of ADCs. 
 
Q33.  Given the extended half-life of an ADC as compared to a cytotoxic small molecule, 
is a single-dose toxicity study using an ADC sufficient to support a clinical dosing 
schedule of once every 3 weeks? (4.7) 
 
At least two doses of the ADC should be administered to support initial  clinical  trials of once 
every 3 or 4 weeks. 
 
Q34.  If the ADC does not bind the target in the nonclinical species, what repeat dose in 
vivo toxicity study would be needed? (4.8) 
 
If the epitope is not present in nonclinical  test species, a toxicology  study in one species for the 
ADC should be sufficient. Alternative models such as transgenic animals or use of a homologous 
molecule is usually  not warranted. 
 
Q35.  What is the utility of tissue distribution studies with an ADC? (4.9) 
 
In general,  tissue distribution  studies of the ADC are not warranted. 
 
Q36.  Generally, two species are used for toxicology testing.  For an ADC, are there 
situations where one species may be acceptable? (4.10) 
 
When the antibody  portion of an ADC binds only to human and NHP antigens, conducting a 
toxicity evaluation  with the ADC in only the NHP (the only relevant species) would be 
appropriate, as discussed in ICH S6(R1).   For  the  payload,  see the response to 
Question 29 (4.3). 
 
Q37.  For metabolites that are human specific or present at disproportionally higher levels 
in humans when compared to toxicology species, what toxicology evaluation should 
be done? (4.11) 
 
In general, additional  studies with disproportional  metabolites  are not needed. In cases where 
the metabolite  is not produced in  toxicology  species and a relatively  high  amount  of 
the human exposure is due to the metabolite and not the active pharmaceutical ingredient (API), 
additional  toxicology  evaluation of human metabolites may be considered. 
 
Q38.  Should impurities exceeding the established qualification limits in ICH Q3A/B be 
assessed in genotoxicity studies:  When the API is genotoxic? When the API is non-
genotoxic? (4.12) 
 
  9  Contains Nonbinding Recommendations 
 
API genotoxic?  Impurity exceeds the  Proposed action 
ICH Q3A/B 
qualification 
threshold? 
Yes  No  None 
Yes  Yes  None 
No  No  None 
No  Yes  Genotoxicity  assessment of 
impurities  should be conducted. 
 
Q39.  Is ICH M7, giving guidance for the management of mutagenic impurities, 
applicable to the patient population covered in the scope of ICH S9? (4.13) 
 
The scope of ICH M7 specifically  states that the guidance does not apply to drug substances 
and drug products intended  for advanced cancer indications  as defined in the scope of ICH 
S9.  Therefore, mutagenic impurities  in products used for treatment of indications  under the 
scope of ICH S9 should be considered for management consistent  with the concepts outlined  in 
ICH Q3A/B (see Question 4.12). 
 
Q40.  Given the compressed development timelines for oncology products, drug substance 
manufacturing processes may not be fully  mature at the time of making the 
marketing application.  If new impurities are observed above ICH Q3A/B 
qualification thresholds after the completion of registration toxicology studies, how 
should such circumstances be handled? (4.14) 
 
ICH Q3A/B gives some flexibility  to qualification  thresholds for impurities  under such 
circumstances. A risk  assessment should  be conducted  (considering  factors like  structural 
similarity  to the parent drug,  toxicology  alerts in the structure, presence of the impurity  at 
lower levels in toxicology  or clinical  lots, metabolite status, patient group and dosing regimen, 
etc.) to consider whether in vivo qualification  studies should be considered.  Such studies may 
not be necessary in all cases just because an impurity  is found above/ is specified above the 
Q3A/B qualification  threshold when the product is being developed under ICH S9. Identifying  a 
no observed adverse effect level in a qualifying  study is usually not warranted. 
 
Q41.  If a drug with an impurity is first developed in patients with late-stage disease, and 
later moves to a different population with long-expected survival (e.g., those 
administered pharmaceuticals on a chronic basis to reduce the risk of recurrence of 
cancer), how should the impurities in the drug be managed? (4.15) 
 
When an anticancer pharmaceutical is further investigated in cancer patient populations with long 
expected survival, ICH Q3A/B and ICH M7 should both be considered for the control of 
impurities. 
 
 
  10  Contains Nonbinding Recommendations 
 
V.  ANNEX: QUESTIONS AND ANSWERS LINKED TO THE RESPECTIVE 
SECTIONS OF ICH S9 GUIDANCE (5) 
 
 
 
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1. Introduction  Scope 
1  1.3          M3(R2) 
S6(R1) 
2  1.3           
3  1.3           
4  1.3    3.4      M3(R2) 
5  1.3           
6  1.3    3.4       
7  1.3    3.4       
2. Studies to Support Nonclinical Evaluation 
1    2.1         
2    2.4         
3    2.4         
4    2.4         
5    2.4         
6    2.4         
7    2.5         
8    2.5         
9    2.5        S6(R1) 
10    2.5         
11    2.6        S2(R1) 
12    2.9        S10 
3. Nonclinical Data to Support Clinical Trial Design and 
Marketing 
1      3.1       
  11  Contains Nonbinding Recommendations 
 
 
 
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2      3.1    Note 2  
3      3.3       
  3.4 
4    2.4 3.4       
5      3.5       
6      3.5       
7      3.5       
4. Other Considerations 
1        4.1     
2        4.1     
3        4.1    S6 (R1) 
4    2.3    4.1     
5    2.3    4.1     
6      3.1  4.1     
7    2.4    4.1     
8      3.1  4.1     
9    2.3    4.1     
10        4.1    S6(R1) 
11        4.3     
12    2.6    4.4     
13    2.6    4.4    M7 
Q3A/B 
14        4.4    Q3A/B 
15        4.4    M7 
Q3A/B 
 
 
 
 
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