Attachment to  
Guidance on 
Pharmacogenomic 
Data Submissions
 
 
Examples of Voluntary Submissions or 
Submissions Required Under 21 CFR 
312, 314, or 601 
 
 
 
 
 
 
 
 
 
 
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) 
Center for Devices and Radiological Health (CDRH) 
March 2005 
Procedural
  Contains Nonbinding Recommendations 
 
 
Pharmacogenomic Data Submissions 
Attachment:  Examples of Required or Voluntary Submissions 
 
 
This attachment to the guidance Pharmacogenomic Data Submissions is intended to illustrate when it would be 
appropriate to submit a voluntary (VGDS) genomic data submission versus a pharmacogenomic data submission 
required under 21 CFR 312, 314, or 601 (RGDS).  Please refer to the complete guidance, or contact the relevant 
center if you have any questions.  Examples for various topic areas are provided using the following format: 
 
Scenario 
Type of Submission 
Rationale 
 
 
Topic Area: Metabolizing Enzymes 
 
Scenario 1:  During IND development, a sponsor conducts single- and multiple-dose pharmacokinetic studies of a 
new molecular entity (NME) in healthy volunteers enrolled to represent the major racial demographic groups.  The 
NME is metabolized primarily by CYP2C19 to inactive metabolites. The sponsor assesses the CYP2C19 genotypes 
in the volunteers to determine the clearance phenotype with the goal of determining if drug dosing needs to be 
individualized based on the genotype groups. 
 
Type of Submission: 
Required in full report (IND)  
 
Rationale: 
The sponsor uses the test results to support scientific arguments pertaining to the pharmacologic mechanism of 
action, the selection of drug dosing or the safety and effectiveness of a drug (as described in Figure A2 of this 
document).     
 
Scenario 2:  A sponsor conducts a phase 3 clinical trial of a NME in patients with the target indication.  The NME 
is metabolized primarily by CYP2D6 to an active metabolite equipotent to the parent molecule.  The sponsor 
genotypes a randomly selected subset of the patients for their CYP2D6 alleles to explore the association between 
genotype, drug dosing, and clinical outcome.  The results show minor differences in clinical outcomes among the 
genotypes. The information is included in the proposed labeling in the NDA submission. 
 
Type of Submission: 
Required in full report (NDA)  
 
Rationale: 
The sponsor included the test results in the drug label (as described in Figure B1 of this document).     
 
Scenario 3:  A sponsor conducts a phase 3 clinical trial of a NME in patients with the target indication.  The NME 
is metabolized primarily by CYP2D6 to an active metabolite equipotent to the parent molecule.  After the trial is 
completed, the sponsor genotypes a randomly selected subset of the patients for their CYP2D6 alleles to explore the 
association between genotype and clearance values. The sponsor will not include the results in the labeling. 
 
Type of Submission: 
Required in abbreviated report (IND or NDA/BLA)  
 
Rationale: 
Although the test results were not used in decision-making or scientific arguments (such as described in Figure A1 
or A2) or in the drug label or as part of the scientific database (such as described in Figure  B1), CYP2D6 is a 
  1 Contains Nonbinding Recommendations 
 
known valid biomarker.  Therefore, the test results must be submitted as an abbreviated report (as described in 
Figure A3, Figure B2 of this document).     
 
Scenario 4:  A sponsor conducts a drug interaction study in healthy volunteers of their NME, a CYP3A substrate, 
co-administered with ketoconazole as an enzyme inhibitor.  Subsequent to the study, the subjects are genotyped for 
their CYP3A5 alleles to determine the relative contribution of this polymorphism to inter-individual variability in 
AUC. 
 
Type of Submission: 
For submissions under an IND, these data could be submitted as a VGDS. For submissions under NDA/BLA, these 
data would be required to be submitted as a synopsis, and a VGDS of the data is encouraged.  
 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or A2) 
or in the drug label or as part of the scientific database (such as described in Figure  B1).  In addition, polymorphism 
of CYP3A5 is not widely studied and is therefore neither a probable or known valid biomarker (such as described in 
Figure A3, B2, or B3).  The information on this genotype is considered to be exploratory (as described in Figure A4 
or B4 of this document).     
 
 
Topic Area: Transporters 
 
Scenario 1:  A sponsor conducts a phase 1 bioavailability study in human volunteers.  The NME is a substrate of 
ABCB1. After the completion of the study, the sponsor genotypes the subjects for their alleles. The data may be 
used to explore causes of inter-individual variability in AUC. 
 
Type of Submission: 
For submissions under IND, these data could be submitted as a VGDS. For submissions under NDA/BLA, these 
data would be required to be submitted as a synopsis, and a VGDS of the data is encouraged. 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or A2) 
or in the drug label or as part of the scientific database (such as described in Figure  B1).  In addition, polymorphism 
of ABCB1 is not well established. Conflicting data on the P-gp activities of various SNPs differ in published reports 
and is therefore neither a probable or known valid biomarker (such as described in Figures A3, B2, or  B3).  The 
information on this genotype is considered to be exploratory (as described in Figure A4 or B4 of this document).     
 
Scenario 2:  During IND development, a sponsor conducts a phase 3 clinical trial of a NME in patients with the 
target indication.  The NME is a substrate of ABCB1.  The sponsor genotypes patients for their ABCB1 alleles prior 
to therapy and uses two different treatment regimens based on genotypes.  
 
Type of Submission: 
Required in full report (IND)  
 
Rationale: 
The test results are used in clinical decision making (affecting dose selection) (as described in Figure A1 of this 
document).     
 
 
Topic Area: Receptors 
 
Scenario 1:  During the IND stage of development, a sponsor reported that, based on a retrospective analysis, 5-
HT1A Ser22 allele was associated with poor response to an SSRI anti-depressant.  In the next clinical trial, the 
sponsor excludes patients with this marker genotype from the trial to enhance the drug's efficacy profile. 
 
  2 Contains Nonbinding Recommendations 
 
Type of Submission: 
Required in full report (IND)  
 
Rationale: 
Data will be used in clinical decision making (entry criteria) (as described in Figure A1). 
 
 
Topic Area: Clinical Outcomes- Efficacy 
 
Scenario 1:  During the IND stage of development, a sponsor of a monoclonal antibody for treatment of an 
autoimmune disease has discovered MHC genetic markers predictive of hypersensitivity reactions upon intravenous 
infusion of the product. The sponsor has also determined that serum concentrations of the antibody 4 weeks after 
infusion are significantly lower among patients who developed initial infusion reactions. The sponsor genotypes the 
MHC markers predictive of infusion reactions in every patient of a prospective clinical study. It is determined that 
patients with the genotypes predictive of infusion hypersensitivity (regardless of whether an infusion reaction 
developed or not) evidence a statistically significantly reduced response to the antibody. The sponsor proposed to 
highlight the improved efficacy demonstration with genetic stratification in the description of the effects of the drug.  
The sponsor excludes patients with this marker genotype from the trial to enhance the drug's efficacy profile. 
 
Type of Submission: 
Required in full report (IND) 
The sponsor is encouraged to develop a pharmacogenomic diagnostic test (unless it is already available), if it to be 
reflected in label.  
 
Rationale: 
Data will be used in clinical decision making (entry criteria) (as described in Figure A2). 
 
Topic Area: Clinical Outcomes- Safety and Efficacy 
 
Scenario 1:   In a clinical trial, psoriatic lesions are biopsied for gene expression profiling of 160 known disease-
associated genes and 140 genes potentially predictive of response for the purpose of comparing gene profiles in 
responders and nonresponders treated with an investigational new drug.  Traditional, core clinical measurements are 
also made to provide evidence of efficacy and safety.  The investigation is intended to identify specific gene 
expression patterns that could possibly be used to correlate with, and predict, efficacy or an adverse event, but at 
present the sponsor does not intend to incorporate the genetic information into labeling 
 
Type of Submission: 
For submissions under IND, these data could be submitted as a VGDS. For submissions under NDA/BLA, these 
data would be required as a synopsis, and a VGDS of the data is encouraged. 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or 
A2).  In addition, these are research data and are therefore neither a probable or known valid biomarker (such as 
described in Figure A3, B2, or B3).  The data are considered to be exploratory (as described in Figure A4 of this 
document).     
 
Scenario 2:  A sponsor filed an IND 3 years ago.  During clinical trials, there was lack of efficacy and so the 
development of the drug was abandoned.  Nevertheless, the drug had some interesting pharmacological actions that 
warranted further investigation by the sponsor.  The sponsor runs a series of genomic studies in rats and dogs with 
the drug and discovers a novel pharmacological profile that leads to plans to develop the drug for a different 
indication. 
 
Type of Submission: 
These data could be submitted as a VGDS. 
 
Rationale: 
  3 Contains Nonbinding Recommendations 
 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or 
A2).  In addition, these are research data and are therefore neither a probable or known valid biomarker (such as 
described in Figure A3).  The data are considered to be exploratory (as described in Figure A4 of this document).     
 
Scenario 2.1 Based on the results of the rat and dog pharmacogenomic studies, the sponsor, during the IND 
stage of development, elects to assess a subset of 25 genes in later clinical trials that may be relevant to the 
safety or efficacy of the compound 
 
Type of Submission: 
Required in full report (IND)  
 
Rationale: 
The sponsor is using the test results to support scientific arguments pertaining to, for example, the 
pharmacologic mechanism of action, the selection of drug dosing or the safety and effectiveness of a drug (as 
described in Figure A2.) 
 
Topic Area: Nonclinical Safety  
 
Scenario 1:  Vasculitis is a major drug-related nonclinical safety signal and the underlying mechanism of toxicity is 
unknown.  It is normally confirmed by histopathology.  A sponsor uses new rat gene chip micro array technology to 
profile 8000 known genes to investigate the mechanism of toxicity and possibly see a pattern of genetic biomarkers 
in treated rats that is different from controls. 
 
Type of Submission: 
For submissions under IND, these data could be submitted as a VGDS. For submissions under NDA/BLA, these 
data would be required as a synopsis, and a VGDS of the data is encouraged. 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or 
A2).  In addition, these are research data and are therefore neither a probable or known valid biomarker (such as 
described in Figure A3, B2, or B3).  The data are considered to be exploratory (as described in Figure A4 of this 
document).     
 
Scenario 2: A sponsor filed an IND 12 months ago.  During the course of subchronic toxicity testing to support 
longer clinical trial designs, the sponsor finds that rats develop cataracts.  This finding represents a safety concern, 
and the sponsor elects to run toxicogenomic studies to define the mechanism of the toxicity.  The sponsor discovers 
that the mechanism is not relevant to humans and uses the data to make their argument about human safety and the 
absence of cataract risk.   
 
Type of Submission: 
Required in full report (IND). 
 
Rationale: 
The sponsor is using the test results to support scientific arguments pertaining to, for example, the pharmacologic 
mechanism of action, the selection of drug dosing or the safety and effectiveness of a drug (as described in Figure 
A2) 
 
Scenario 3:   During the IND stage of development, a sponsor is investigating a new drug class and seeks to select 
for clinical development the best of 20 drugs showing some promise in their efficacy screen.  No IND has yet been 
filed.  The sponsor elects to assess differences in gene expression profiles to help with prioritization.  The data may 
be generated from animal studies or from cell culture studies.  The sponsor feels that the comparative profiles of 
gene expression alterations between the 20 drugs may help to select the most effective agent with least potential for 
toxicity.  The data are generated to assist with compound selection and are not intended to support the safety of a 
proposed clinical investigation. 
 
Type of Submission: 
  4 Contains Nonbinding Recommendations 
 
These data could be submitted as a VGDS (IND). 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or 
A2).  In addition, these are research data and are therefore neither a probable or known valid biomarker (such as 
described in Figure A3).  The data are considered to be exploratory (as described in Figure A4 of this document).     
 
Scenario 4:  During the IND stage of development, a sponsor completes a 2-year carcinogenicity assay in rats and 
finds that there is an ambiguous tumor signal generated in the kidney, a site that is generally resistant to tumor 
induction.  The sponsor elects to prove that the event was a spontaneous event that was not drug related by dosing 
the same strain of rats with drug.  The sponsor succeeds in showing that there is no effect of the drug on gene 
expression in the kidney.  A positive control shows a gene expression profile that is very consistent with known 
pathways of carcinogenesis.  The data are used to argue to regulatory authorities that the drug is safe and does not 
present a tumorigenic risk to humans. 
 
Type of Submission: 
Required as full report (IND). 
 
Rationale: 
The sponsor is using the test results to support scientific arguments pertaining to, for example, the pharmacologic 
mechanism of action, the selection of drug dosing, or the safety and effectiveness of a drug (as described in Figure 
A2). 
 
 
Scenario 5:  A sponsor conducts global gene expression analyses to assess the relationship between dose and target 
organ effect.  Their drug is a novel acting antipsychotic agent.  The sponsor has experience that indicates that the 
dose-limiting effect of their drug candidate will probably injure the kidneys  an insidious chronic progressive 
nephropathy.  Using pharmacogenomic analyses, the sponsor finds that reliable and reproducible effects on kidney 
gene expression occur in both rats and dogs at a dose that is 20-fold lower than the doses in 30-day studies causing a 
demonstrable histopathology lesion or changes in serum markers for renal toxicity.   Insufficient information is 
currently available to definitively link the more sensitive dose-response changes in gene expression patterns to 
future changes in renal function or histopathologic lesions.  
 
Type of Submission: 
For submissions under IND, these data could be submitted as a VGDS. For submissions under NDA/BLA, these 
data would be required as a synopsis, and a VGDS of the data is encouraged. 
 
Rationale: 
The test results are not being used in decision-making or scientific arguments (such as described in Figure A1 or 
A2).  In addition, these are research data and are therefore neither a probable or known valid biomarker (such as 
described in Figure A3, B2, or B3).  The data are considered to be exploratory (as described in Figure A4 or B4 of 
this document).     
 
  5 Contains Nonbinding Recommendations 
 
GLOSSARY 
 
The following definitions are for use in the processes outlined in this guidance and are not intended to be broadly 
applicable to the entire field. 
 
Biological marker (biomarker):  A characteristic that is objectively measured and evaluated as an indicator of 
normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.1 
 
Pharmacogenetic test:  An assay intended to study interindividual variations in DNA sequence related to drug 
absorption and disposition (pharmacokinetics) or drug action (pharmacodynamics), including polymorphic variation 
in the genes that encode the functions of transporters, metabolizing enzymes, receptors, and other proteins 
 
Pharmacogenomic test:  An assay intended to study interindividual variations in whole-genome or candidate gene, 
single-nucleotide polymorphism (SNP) maps, haplotype markers, or  alterations in gene expression or inactivation 
that may be correlated with pharmacological function and therapeutic response.  In some cases, the pattern or profile 
of change is the relevant biomarker, rather than changes in individual markers. 
 
Valid biomarker:  A biomarker that is measured in an analytical test system with well-established performance 
characteristics and for which there is an established scientific framework or body of evidence that elucidates the 
physiologic, toxicologic, pharmacologic, or clinical significance of the test results.  The classification of biomarkers 
is context specific.  Likewise, validation of a biomarker is context-specific and the criteria for validation will vary 
with the intended use of the biomarker.  The clinical utility (e.g., predict toxicity, effectiveness or dosing) and use of 
epidemiology/population data (e.g., strength of genotype-phenotype associations) are examples of approaches that 
can be used to determine the specific context and the necessary criteria  for validation. 
 
  Known valid biomarker:  A biomarker that is measured in an analytical test system with well-
established performance characteristics and for which there is widespread agreement in the medical or 
scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the 
results 
 
  Probable valid biomarker:  A biomarker that is measured in an analytical test system with well-
established performance characteristics and for which there is a scientific framework or body of 
evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance 
of the test results.  A probable valid biomarker may  , not have reached the status of a known valid 
marker because, for example, of any one of the following reasons: 
  The data elucidating its significance may have been generated within a single company and may 
not be available for public scientific scrutiny. 
 The data elucidating its significance, although highly suggestive, may not be conclusive. 
 Independent verification of the results may not have occurred.  
 
Voluntary genomic data submission (VGDS):  The designation for pharmacogenomic data submitted voluntarily 
to the FDA.
                                                           
1 Biomarkers Definitions Working Group, "Biomarkers and Surrogate Endpoints:  Preferred Definitions and 
Conceptual Framework," Clinical Pharm. & Therapeutics, vol. 69, N. 3, March 2001.  
  6 Contains Nonbinding Recommendations 
 
 
Figure A:  Submission of Pharmacogenomic (PG) Data to an IND 
 
Reports of pharmacogenomic investigations should be submitted to the IND in accordance with the decision tree below and in the formats indicated here or in the 
body of the guidance: 
 
 
  Animal or human PG Study Results 
 
 
 
 
  Y
 
 
Meets  
  IND 
1 or 2, below?  Full report to 
 
 
 
 
 
  N 
 
 
  Y IND 
  Abbreviated report to 
Meets  
 
3, below? 
 
 
 
 
 
N 
 
 
No required submission needed; VGDS encouraged 
 
 
 
 
Pharmacogenomic data must be submitted to the IND under  312.23 if ANY of the following apply: 
 
1.  The test results are used for making decisions pertaining to a specific clinical trial, or in a animal trial used to support safety (e.g., the results will 
affect dose selection, entry criteria into a clinical trial safety monitoring, or subject stratification).  
  7 Contains Nonbinding Recommendations 
 
2.  A sponsor is using the test results to support scientific arguments pertaining to the pharmacologic mechanism of action, the selection of drug dosing 
or the safety and effectiveness of a drug. 
3.  The test results constitute a known, valid biomarker for physiologic, pathophysiologic, pharmacologic, toxicologic, or clinical states or outcomes in 
humans, or is a known valid biomarker for a safety outcome in animal studies, or a probable valid biomarker in human safety studies.  If the 
information on the biomarker (example, human CYP2D6 status) is not being used for purposes 1 or 2 above, the information can be submitted to 
the IND as an abbreviated report. 
 
Submission to an IND is NOT needed, but voluntary submission is encouraged (i.e., information does not meet the criteria of  312.23) if 
 
4.  Information is from exploratory studies or is research data, such as from general gene expression analyses in cells/animals/humans, or single-
nucleotide polymorphism (SNP) analysis of trial participants.  
5.  Information consists of results from test systems where the validity of the biomarker is not established.
  8 Contains Nonbinding Recommendations 
 
 
Figure B:  Submission of Pharmacogenomic (PG) Data To A New NDA, BLA, or Supplement 
 
Reports of pharmacogenomic investigations should be submitted to the NDA in accordance with the decision tree below and in the formats indicated here or in 
the body of the guidance: 
 
 
 
  Animal or human PG study results 
 
 
 
 
 
Y
 
  Meets  
  1, below?  Full report in NDA/BLA 
 
 
 
 
 
N 
 
 
  Y
  Meets 2, or 3, 
  below?  Abbreviated report to NDA/BLA
 
 
 
 
  N 
 
  Synopsis to NDA/BLA; VGDS encouraged 
   
 
 
  9 Contains Nonbinding Recommendations 
 
1.  The sponsor will use the test results in the drug label or as part of the scientific database being used to support approval as complete submissions (not in 
the form of an abbreviated report, synopsis, or VGDS), including information about test procedures and complete data, in the relevant sections of the 
NDA or BLA.  If the pharmacogenomic test is already approved by the FDA or is the subject of an application filed with the Agency, information on the 
test itself can be provided by cross reference.   
The following examples would fit this category.   
 Pharmacogenomic test results that are being used to support scientific arguments made by the sponsor about drug dosing, safety, patient selection, 
or effectiveness  
 Pharmacogenomic test results that the sponsor proposes to describe in the drug label 
 Pharmacogenomic tests that are essential to achieving the dosing, safety, or effectiveness described in the drug label 
2.  The test results are known valid biomarkers for physiologic, pathophysiologic, pharmacologic, toxicologic, or clinical states or outcomes in the relevant 
species, but the sponsor is not relying on or mentioning this in the label.  Submit to the Agency as an abbreviated report (not as a synopsis or VGDS).  If 
a pharmacogenomic test of this type was conducted as part of a larger overall study, the reporting of the pharmacogenomic test results can be 
incorporated into the larger study report. 
3.  The test results represent probable valid biomarkers for physiologic, pathophysiologic, pharmacologic, toxicologic, or clinical states or outcomes in the 
relevant species.  Submit to the Agency as an abbreviated report.  If the pharmacogenomic testing of this type was conducted as part of a larger study, 
the abbreviated report can be appended to the report of the overall study. 
4.  Information from general exploratory or research studies, such as broad gene expression screening, collection of sera or tissue samples, or results of 
pharmacogenomic tests that are not known or probable valid biomarkers to the NDA or BLA are not required to be submitted.  Because the Agency 
does not view these studies as germane in determining the safety or effectiveness of a drug, the submission requirements in  314.50 or 601.2 will be 
satisfied by the submission of a synopsis of the study.  However, the Agency encourages the voluntary submission of the data from the study in a VGDS 
submitted to the NDA or BLA.
  10 Contains Nonbinding Recommendations 
 
Figure C:  Submission of Pharmacogenomic (PG) Data to an Approved  
NDA, BLA, or Supplement 
 
 
 
  Animal or human PG study results 
 
 
 
 
 
Y
 
 
  Known or probable  Abbreviated report or synopsis 
  valid biomarkers? 
 
 
 
 
N 
 
 
  No required submission needed; VGDS encouraged 
 
  11