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 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.
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:
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:
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).
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.
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.
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:
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).
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.
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:
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.