Voluntary Genomic Data Submissions

Guidance for Industry
Pharmacogenomic Data
Submissions

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

Guidance for Industry
Pharmacogenomic Data
Submissions
Additional copies are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
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http://www.fda.gov/cber/guidelines.htm.
(Tel) Voice Information System at 800-835-4709 or 301-827-1800
Office of Health and Industry Programs
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Center for Devices and Radiological Health
Food and Drug Administration
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Rockville, MD 20850-4307 U.S.A.
http://www.fda.gov/cdrh/ggpmain.html
Email: [email protected]
Fax: 301.443.8818
(Tel) Manufacturers Assistance: 800.638.2041 or 301.443.6597
(Tel) International Staff Phone: 301.827.3993

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

TABLE OF CONTENTS

I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

III.

SUBMISSION POLICY................................................................................................... 3

A.

General Principles.......................................................................................................................... 3

B.

Specific Uses of Pharmacogenomic Data in Drug Development and Labeling ........................ 5

C.

Benefits of Voluntary Submissions to Sponsors and FDA ......................................................... 7

IV.

SUBMISSION OF PHARMACOGENOMIC DATA.................................................... 8

A.

Submission of Pharmacogenomic Data During the IND Phase ................................................. 8

B.

Submission of Pharmacogenomic Data to a New NDA, BLA, or Supplement ....................... 10

C.

Submission to a Previously Approved NDA or BLA ................................................................ 11

D.

Compliance with 21 CFR Part 58............................................................................................... 11

E.

Submission of Voluntary Genomic Data from Application-Independent Research.............. 12

V.

FORMAT AND CONTENT OF A VGDS.................................................................... 12

VI.

PROCESS FOR SUBMITTING PHARMACOGENOMIC DATA .......................... 14

VII.

AGENCY REVIEW OF VOLUNTARY GENOMIC DATA SUBMISSIONS ....... 14

GLOSSARY................................................................................................................................. 17
APPENDIX A: SUBMISSION OF PHARMACOGENOMIC (PG) DATA TO AN IND... 19
APPENDIX B: SUBMISSION OF PHARMACOGENOMIC (PG) DATA TO A NEW
NDA, BLA, OR SUPPLEMENT ............................................................................................... 21
APPENDIX C: SUBMISSION OF PHARMACOGENOMIC (PG) DATA TO AN
APPROVED NDA, BLA, OR SUPPLEMENT ........................................................................ 23
APPENDIX D: QUICK REFERENCE ON PHARMACOGENOMIC SUBMISSIONS ... 24
APPENDIX E: VOLUNTARY SUBMISSION COVER SHEET .......................................... 25

Contains Nonbinding Recommendations

Guidance for Industry1
Pharmacogenomic Data Submissions

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance is intended to facilitate scientific progress in the field of pharmacogenomics and to
facilitate the use of pharmacogenomic data in drug development. The guidance provides
recommendations to sponsors holding investigational new drug applications (INDs), new drug
applications (NDAs), and biologics license applications (BLAs) on (1) when to submit
pharmacogenomic data to the Agency during the drug or biological drug product2 development
and review processes, (2) what format and content to provide for submissions, and (3) how and
when the data will be used in regulatory decision making. Key information, including examples
of when pharmacogenomic data submissions would be required and when voluntary genomic
data submissions (VGDSs) would be welcome are provided in a separate companion document
(Pharmacogenomic Data Submissions, Attachment: Examples of Voluntary Submissions or
Submissions Required Under 21 CFR 312, 314, or 601).
For the purposes of this guidance, the term pharmacogenomics is defined as the use of a
pharmacogenomic or pharmacogenetic test (see glossary for definitions) in conjunction with
drug therapy. Pharmacogenomics does not include the use of genetic or genomic techniques for
the purposes of biological product characterization or quality control (e.g., cell bank
characterization, bioassays). The FDA plans to provide guidance on those uses at a future time.
Pharmacogenomics also does not refer to data resulting from proteomic or metabolomic
1

This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER), in cooperation with the Center for Devices and Radiological Health
(CDRH) at the Food and Drug Administration.
2

For the purposes of this guidance, the term drug or drug product includes human drug and biological products.

Paperwork Reduction Act Public Burden Statement: According to the Paperwork Reduction Act of 1995, a
collection of information should display a valid OMB control number. The valid OMB control number for this
information collection is 0910-0557 (expires 12/31/2007). The time required to complete this information collection
is estimated to average 10 hours per response, including the time to review instructions, search existing data
resources, gather the data needed and complete and review the information collection.

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techniques. This document is not meant to provide guidance on pharmacoproteomics or
multiplexed protein analyte based technologies. However, the voluntary submission process
described in this guidance may be used to submit such data if so desired.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's 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

The promise of pharmacogenomics lies in its potential to help identify sources of inter-individual
variability in drug response (both effectiveness and toxicity); this information will make it
possible to individualize therapy with the intent of maximizing effectiveness and minimizing risk.
However, the field of pharmacogenomics is currently in early developmental stages, and such
promise has not yet been realized. The Agency has heard that pharmaceutical sponsors have been
reluctant to embark on programs of pharmacogenomic testing during FDA-regulated phases of
drug development because of uncertainties in how the data will be used by FDA in the drug
application review process. This guidance is intended to help clarify FDA policy in this area.
Sponsors submitting or holding INDs, NDAs, or BLAs are subject to FDA requirements for
submitting to the Agency data relevant to drug safety and effectiveness (including 21 CFR
312.22, 312.23, 312.31, 312.33, 314.50, 314.81, 601.2, and 601.12). Because these regulations
were developed before the advent of widespread animal or human genetic or gene expression
testing, they do not specifically address when such data must be submitted. The FDA has
received numerous inquiries about what these regulations require of sponsors who are
conducting such testing.
From a public policy perspective, a number of factors should be considered when interpreting
how these regulations apply to the developing field of pharmacogenomics. Because the field of
pharmacogenomics is rapidly evolving, in many circumstances, the experimental results may not
be well enough established scientifically to be suitable for regulatory decision making. For
example:
•

Laboratory techniques and test procedures may not be well validated. In addition, test
systems may vary so that results may not be consistent or generalizable across different
platforms. A move to standardize assays is underway, and much more information
should be available within the next several years.

•

The scientific framework for interpreting the physiologic, toxicologic, pharmacologic, or
clinical significance of certain experimental results may not yet be well understood.

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•

The findings from a specific study often cannot be extrapolated across species or to
different study populations (e.g., various human subpopulations with different genetic
backgrounds).

•

The standards for transmission, processing, and storage of the large amounts of highly
dimensional data generated from microarray technology have neither been well defined
nor widely tested.

Despite these concerns, some pharmacogenetic tests — primarily those related to drug
metabolism — have well-accepted mechanistic and clinical significance and are currently being
integrated into drug development decision making and clinical practice.
It is important for FDA to have a role in the evaluation of pharmacogenomic tests, both to ensure
that evolving FDA policies are based on the best science and to provide public confidence in the
field. The FDA developed this guidance to facilitate the use of pharmacogenomic tests during
drug development and encourage open and public sharing of data and information on
pharmacogenomic test results.
To this end, the Agency has undertaken a process for obtaining input from the scientific
community and the public. On May 16 and 17, 2002, the Agency held a workshop, cosponsored
by pharmaceutical industry groups, to identify key issues associated with the application of
pharmacogenetics and pharmacogenomics to drug development. Subsequently, on April 8, 2003,
a public presentation was made to the FDA Science Board. This presentation contained a
proposal for developing guidance on the submission of information on pharmacogenomic tests
and a potential algorithm for deciding whether submission of such data is voluntary or required.
The Science Board endorsed moving forward with both of these proposals. In November 2003,
FDA published a draft version of this guidance and received public comment on the draft
guidance. The Agency also has developed internal policy related to pharmacogenomics and
voluntary submissions.3
The policies and processes outlined in this final guidance are intended to take the above factors
into account and to assist in advancing the field in a manner that will benefit both drug
development programs and the public health.

III.

SUBMISSION POLICY
A.

General Principles

The FDA recognizes that its pharmacogenomic data submission policies must be consistent with the
relevant codified regulatory submission requirements for investigational and marketing application
submitters and holders. At present, many pharmacogenomic results are not well enough established
3

A charter has been developed outlining the organization, principles, and function of the inter-center
Interdisciplinary Pharmacogenomics Review Group (IPRG) (MaPP 4180.2). In addition, policy has been developed
for Agency staff, explaining how voluntary genomic data submissions (VGDSs) will be received and reviewed in
the Agency (MaPP 4180.3; SOPP 8114).

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scientifically to be appropriate for regulatory decision making.4 This guidance interprets FDA's
regulations for investigational and marketing submissions, with the goal of clarifying FDA's current
thinking about when the regulations require pharmacogenomic data to be submitted and when the
submission of such data would be welcome on a voluntary basis. In some cases, complete reports of
pharmacogenomic studies suffice, while in others, an abbreviated report or synopsis should or must
be submitted.5
Because FDA regulations establish different requirements for investigational applications,
unapproved marketing applications, and approved marketing applications, this guidance sets out
different submission algorithms for each of these categories. The guidance also clarifies how the
Agency currently intends to use such data in regulatory decision making — that is, when the data will
be considered sufficiently reliable to serve as the basis for regulatory decision making; when it will
be considered only supportive to a decision; and when the data will not be used in regulatory decision
making.
This guidance also makes a distinction between pharmacogenomic tests that may be considered either
probable or known valid biomarkers, which may be appropriate for regulatory decision making, and
other less well-developed tests that are either observational or exploratory biomarkers that, alone, are
insufficient for making regulatory decisions. Although, currently, most pharmacogenomic
measurements are not considered valid biomarkers, certain markers (e.g., for drug metabolism) are
well established biomarkers with clear clinical significance. Undoubtedly, the distinction between
what tests are appropriate for regulatory decision making and those that are not will change over time
as the science evolves. Throughout the development of these tests, as appropriate, FDA will continue
to seek public comment as we evaluate whether a biomarker is a valid biomarker (e.g., via
discussions at Advisory Committee meetings).
For the purposes of this guidance, a pharmacogenomic test result may be considered a valid
biomarker if (1) it is measured in an analytical test system with well-established performance
characteristics and (2) there is an established scientific framework or body of evidence that
elucidates the physiologic, pharmacologic, toxicologic, or clinical significance of the test results.
For example, the consequences for drug metabolism of genetic variation in the human enzymes
CYP2D6 and thiopurine methyltransferase are well understood in the scientific community and
are reflected in certain approved drug labels. The results of genetic tests that distinguish allelic
variants of these enzymes are considered to be well established and, therefore, valid biomarkers.
This guidance makes an additional distinction between known valid biomarkers that have been
accepted in the broad scientific community and probable valid biomarkers that appear to have
predictive value for clinical outcomes, but may not yet be widely accepted or independently
verified by other investigators or institutions (see Glossary). When a sponsor generates, or
4

For purposes of this document, the term regulatory decision making, as defined here, applies to decisions that FDA
may make in the evaluation of pharmacogenomic information used to establish the dosing, safety, or effectiveness of
a drug or biological product. FDA regulatory decisions occur throughout the investigational stages of product
development, during premarket review, and during postmarket regulation.
5

For further information on when abbreviated study reports can be submitted in NDAs and BLAs, see the guidance
for industry Submission of Abbreviated Reports and Synopses in Support of Marketing Applications, developed
under section 118 of the Food and Drug Administration Modernization Act.

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Contains Nonbinding Recommendations
possesses, data sufficient to establish a significant association between a pharmacogenomic test
result and clinical outcomes, the test result represents a probable valid biomarker. It would be
expected that this biomarker would meet criteria (1) and (2) above, and its association with a
meaningful outcome would have been demonstrated in more than one experiment.
The algorithms described below for investigational and marketing application holders describe
when to submit to FDA data on known valid biomarkers. Data on probable valid biomarkers
need not be submitted to the IND unless they are used by a sponsor to make decisions regarding
specific animal safety studies or clinical trials (e.g., using biomarker data as inclusion or
exclusion criteria, assessment of treatment-related prognosis, or stratifying patients by dose) or
are a probable valid biomarker in human safety studies (see section IV.A).6 However, we
recommend that sponsors or applicants submit reports on all probable valid biomarkers to new
(i.e., unapproved) NDAs or BLAs according to the algorithm in section IV.B.
Many pharmacogenomic testing programs implemented by pharmaceutical sponsors or by
scientific organizations are intended to develop the knowledge base necessary to establish the
validity of new genomic biomarkers. During such a period of scientific exploration, test results
are not useful in making regulatory judgments pertaining to the safety or effectiveness of a drug
and are not considered known or probable valid biomarkers. However, scientific development of
this sort is highly desirable for advancing the understanding of relationships between genotype or
gene expression and responses to drugs and, therefore, should be encouraged and facilitated. For
these reasons, although submission of exploratory pharmacogenomic data is not required under
the regulations, FDA is encouraging voluntary submission of such data, as described below.
B.

Specific Uses of Pharmacogenomic Data in Drug Development and Labeling

As the field of pharmacogenomics advances, it is likely (and desirable) that sponsors will begin
to use pharmacogenomic tests to support drug development and/or to guide therapy. Sponsors
may choose to submit pharmacogenomic data that have not achieved the status of a valid
biomarker to an investigational or marketing application to support scientific contentions related
to dosing and dosing schedule, safety, or effectiveness. For example, a sponsor may wish to
provide supportive data demonstrating that changes in drug-induced gene expression differ
between species that have different toxicologic responses to a drug, thus correlating changes in
certain gene expression patterns with a specific toxicity. Or, a pharmacogenomic test result
might also be used to stratify patients in a clinical trial or to identify patients at higher risk for an
adverse event to correlate test results with clinical outcome.
When pharmacogenomic results affect the design of a specific animal safety trial, or human
safety or efficacy trial, the submission algorithms described below suggest that full information
on the test system must be submitted to the IND (§§ 312.30(b) and 312.31). In contrast, results
from earlier feasibility studies done under the same IND (or outside the IND) to establish the
potential usefulness of the pharmacogenomic test (e.g., from samples taken during a doseresponse study) are not a required submission, but would be encouraged as a voluntary
6

For the purposes of this guidance, the phrase decision making by the sponsor, as defined here, refers to study- or
trial-specific decisions that a sponsor might make in the development of a drug, but not to overall strategies related
to drug development or portfolio management.

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Contains Nonbinding Recommendations
submission. However, a plan to perform any invasive test, including phlebotomy, with the
possible intent to conduct pharmacogenomic testing on a sample, must be noted both in the
protocol and the informed consent document (§§ 312.23(a)(6), 312.30(b), and 50.25).
If a pharmacogenomic test shows promise for enhancing the dose selection, safety, or
effectiveness of a drug, a sponsor may wish to fully integrate pharmacogenomic data into the
drug development program. This integration could occur in two ways:
1.

The pharmacogenomic data may be intended to be included in the drug labeling in an
informational manner.
For example, such data might be used to describe the potential for dose adjustment by
drug metabolism genotype (e.g., CYP2D6*5) or to mention the possibility of a side effect
of greater severity or frequency in individuals of a certain genotype or gene expression
profile. In such cases, the pharmacogenomic test result would be considered a known
valid biomarker. However, an FDA-approved pharmacogenomic test may not be
available or required to be available, or a commercial pharmacogenomic test may not be
widely available. Given this level of complexity, at the current time, sponsors should
consult the relevant FDA review division for advice on how to proceed in a specific case.
However, whenever a sponsor intends to include pharmacogenomic data in the drug label,
complete information on the test and results must be submitted to the Agency as
described under §§ 314.50 and 601.2.

2.

The pharmacogenomic data and resulting test or tests may be intended to be included in
the drug labeling to choose a dose and dose schedule, to identify patients at risk, or to
identify patient responders. Inclusion of a pharmacogenomic test in the labeling would
be contingent upon its performance characteristics. For example:
•

Patients will be tested for drug metabolism genotype and dosed according to the test
results.

•

Patients will be selected as potential responders for an efficacy trial (or deselected
because of a high risk) based on genotype (e.g., of either the patient or the patient’s
tumor) or gene expression profile.

•

Patients will be excluded from a clinical trial based on genotype or gene expression
profile (e.g., biomarker for risk of an adverse event).

In all of these cases, FDA recommends co-development of the drug and the
pharmacogenomic tests, if they are not currently available, and submission of complete
information on the test/drug combination to the Agency. The FDA plans to issue further
guidance on co-development of pharmacogenomic tests and drugs.
The Office of In Vitro Diagnostics in CDRH, appropriate review divisions in CBER, and
the Clinical and Clinical Pharmacology Review divisions in CBER or CDER are willing
to meet jointly with sponsors to discuss both scientific and regulatory issues with regard
to new pharmacogenomic tests. The CDRH has both formal (IDE) and informal (preIDE) processes to evaluate protocols for pharmacogenomic test development.

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C.

Benefits of Voluntary Submissions to Sponsors and FDA

At the current time, most pharmacogenomic data are of an exploratory or research nature, and
FDA regulations do not require that these data be submitted to an IND, or that complete reports
be submitted to an NDA or BLA. However, voluntary submissions can benefit both the industry
and FDA in a general way by providing a means for sponsors to ensure that regulatory scientists
are familiar with and prepared to appropriately evaluate future genomic submissions. The FDA
and industry scientists alike would benefit from an enhanced understanding of relevant scientific
issues, such as the following:
•

The types of genetic loci or gene expression profiles being explored by the
pharmaceutical industry for pharmacogenomic testing

•

The test systems and techniques being employed

•

The problems encountered in applying pharmacogenomic tests to drug development

•

The ability to transmit, store, and process large amounts of complex pharmacogenomic
data streams with retention of fidelity

•

The scientific rationale for standardizing naming and characterization of the genes used
on different genomic analysis platforms and for developing bioinformatics software
programs used to evaluate pharmacogenomic data

•

Facilitate identification of predictors of safety, effectiveness, or toxicity

A greater understanding of the issues surrounding the use of pharmacogenomic data may prevent
delays in reviews of future submissions where genomics are an integral part of specific studies in
a drug development program.
Therefore, FDA is requesting that sponsors conducting such programs consider providing
pharmacogenomic data to the Agency voluntarily, when such data are not otherwise required
under the regulations. To facilitate VGDSs, FDA has established a cross-center Interdisciplinary
Pharmacogenomic Review Group (IPRG) to review VGDSs, to work on policy development,
and, upon request, to advise review divisions on interpretation and evaluation of
pharmacogenomic data.
For sponsors, voluntary submission of genomic data offers a number of specific potential
benefits:
•

Meet informally with FDA and receive peer review assessments of scientific data from
pharmacogenomic experts at the Agency

•

Obtain insight into the evolving regulatory decision making process as it relates to
genetic and genomic information

•

Familiarize FDA scientists with novel pharmacogenomic experiments, data analysis, and
interpretation approaches at an early stage

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IV.

•

Conserve time and resources by obtaining feedback from FDA on a VGDS that might
highlight unaddressed issues that could prove time consuming or costly later during
product development

•

Identify new opportunities for drug development (e.g., feedback from FDA might help
reach new strategic decisions). For example, a shelved product may be continued when
new tools such as genotyping assays become available to demonstrate effectiveness in a
subpopulation.

•

Make a contribution to the VGDS data repository to facilitate advancement of
pharmacogenomics and development of rational, data-based policies and guidances
SUBMISSION OF PHARMACOGENOMIC DATA

The FDA's regulations establish different requirements for INDs, new (i.e., unapproved) NDAs
and BLAs, and approved NDAs and BLAs. For this reason, there are different submission
algorithms for the submission of pharmacogenomic data.
A.

Submission of Pharmacogenomic Data During the IND Phase

Section 312.23 describes information submission requirements for an IND, including data
generated or available during the IND phase. Section 312.23(a)(8) contains the requirements for
pharmacology and toxicology information: “Adequate information about pharmacologic and
toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which
the sponsor has concluded that it is reasonably safe to conduct the proposed clinical
investigations” (emphasis added). The in vitro and animal studies needed to establish a basis for
proceeding with human trials of various types are well established internationally. Therefore,
pharmacogenomic data relevant to, or derived from, animal or in vitro studies must ordinarily be
submitted according to § 312.23(a)(8) when the sponsor wishes to use these data to make a
scientific case, or when the pharmacogenomic test is a known valid biomarker.
Section 312.23(a)(9) sets forth the requirements for submitting previous human experience with
an investigational drug. The application must include a summary of trials or human experience
relevant to an evaluation of the safety or effectiveness of a drug. Therefore, sponsors must
submit human data of known relevance (e.g., known valid pharmacogenomic biomarkers). In
addition, sponsors or applicants must submit "any other information that would aid evaluation of
the proposed clinical investigations with respect to their safety or their design and potential as
controlled clinical trials to support the marketing of the drug" (§ 312.23(a)(10)(iv)). Sponsors
may possess human data that suggest that a particular biomarker is a probable valid biomarker
for evaluating the safety of the drug being evaluated. In these cases, information on the
biomarker must be submitted to the IND because it could potentially aid in evaluation of the
safety of the investigations per the regulations.
In addition, section 312.23(a)(11) states that a sponsor must submit "if requested by FDA, any
other relevant information needed for review of the application." Therefore, during the IND
review, FDA may request pharmacogenomic information the Agency considers relevant (e.g.,
information related to the mechanism of action of the drug).
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Contains Nonbinding Recommendations

Sponsors holding INDs who generate or possess pharmacogenomic data related to an
investigational drug can comply with FDA requirements using the following algorithm:
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
an animal trial used to support safety (e.g., the results will affect dose and dose schedule
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, for
example, the pharmacologic mechanism of action, the selection of drug dosing and
dosing schedule, or the safety and effectiveness of a drug.
3. Test results constitute a known valid biomarker for physiologic, pathophysiologic,
pharmacologic, toxicologic, or clinical states or outcomes in humans, or the test is a
known valid biomarker for a safety outcome in animal 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 required, 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.
Although submission of such data in cases 4 and 5 is not required under the regulations, FDA
would welcome voluntary submission of the data in a VGDS. See Appendix A for additional
guidance on assessing whether to submit pharmacogenomic data to an IND.
Note: Regardless of requirements for submission, the fact that samples will be collected for
potential analysis must be noted in any clinical protocol (§ 312.23(a)(6)) and informed consent
documents (§ 50.25).
Data from a VGDS submission concerning a product under an IND will not be used for
regulatory decision making. However, after the sponsor submits a VGDS, if additional
information becomes available that triggers the requirements for submission under §§ 312, 314,
or 601, the sponsor must submit the data to the relevant application and should follow the
appropriate algorithm.

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B.

Submission of Pharmacogenomic Data to a New NDA, BLA, or Supplement

Section 314.50 outlines the NDA submission requirements; section 601.2 generally outlines
BLA submission requirements. As the introduction to § 314.50 states, “the [NDA] application is
required to contain reports of all investigations of the drug product sponsored by the applicant,
and all other information about the drug product pertinent to an evaluation of the application that
is received or otherwise obtained by the applicant from any source.” Therefore, to comply with
these regulations, sponsors must provide reports of certain pharmacogenomic investigations in
their NDAs, and to permit a thorough analysis of a biologics application, a sponsor must submit
such a report in its BLA. However, the extent and format of such reports will depend on the
relevance and application of the information.
Subsequent paragraphs of § 314.50 outline the submission requirements in specific disciplines.
Nonclinical pharmacology and toxicology submission requirements are described in § 314.50(d)(2);
human pharmacokinetics and bioavailability requirements in § 314.50(d)(3); and clinical data
requirements in § 314.50(d)(5).
Section 601.2 generally outlines the BLA submission requirements. Section 601.2 states that the
BLA manufacturer shall submit data derived from nonclinical laboratory and clinical studies that
demonstrate that the manufactured product meets prescribed requirements of safety. Like NDA
sponsors, BLA sponsors must provide reports of certain pharmacogenomic investigations in their
BLAs. However, the extent and format of such reports will depend on the relevance and
application of the information.
Sponsors who have generated or possess pharmacogenomic data related to a drug can comply
with the regulations' requirements using the algorithm below describing what kind of report to
submit:
1. Provide full (complete) reports on pharmacogenomic investigations intended by the
sponsor to be used 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 FDA or is the subject of an application submitted to the Agency,
information on the test itself can be provided by cross reference.
The following examples would fit this category.
•

Pharmacogenomic test results from clinical trials used to support scientific
arguments made by the sponsor about selecting drug doses, assessing safety,
selecting patients for treatment, or monitoring the beneficial responses

•

Pharmacogenomic test results that the sponsor proposes to describe in the drug
labeling

•

Pharmacogenomic tests that are essential to achieving the dosing, safety, or
effectiveness described in the drug labeling

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2. Submit reports of pharmacogenomic test results that constitute known valid biomarkers
for physiologic, pathophysiologic, pharmacologic, toxicologic, or clinical states or
outcomes in the relevant species, but that the sponsor is not relying on or mentioning in
the label, to the Agency as an abbreviated report (not in the form of 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. Submit reports of pharmacogenomic tests that represent probable valid biomarkers for
physiologic, pathophysiologic, pharmacologic, toxicologic, or clinical states or outcomes
in the relevant species to the NDA or BLA 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. There is no need to submit detailed reports of general exploratory or research information,
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. Because the Agency does not view such studies as germane in determining the
safety or effectiveness of a product, 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 such a study in a VGDS.
See Appendix B for additional guidance on how to assess whether to submit pharmacogenomic
data to an unapproved NDA or BLA.
C.

Submission to a Previously Approved NDA or BLA

The requirements for submitting new scientific information to a previously approved NDA or
BLA are outlined in §§ 314.81(b)(2) and 601.12. Results of nonclinical or clinical
pharmacogenomic investigations on known or probable valid biomarkers must be submitted in
the annual report as synopses or abbreviated reports (§ 314.81(b)(2)).
Pharmacogenomic study results of other types do not meet the submission requirements outlined
in the regulations (§ 314.81(b)(2)). However, such reports can be voluntarily submitted to the
NDA or BLA as a VGDS.
Pharmacogenomic data collected in pharmacoepidemiologic and observational studies can be
submitted as a VGDS by the applicant in accordance with the recommendations in this guidance
(see Section VI).
D.

Compliance with 21 CFR Part 58

Questions have been raised about the need for pharmacogenomic studies to comply with the
requirements of 21 CFR part 58, which describes good laboratory practices (GLPs) for
nonclinical laboratory studies that support INDs and NDAs. Section 58.3(d) (21 CFR 58.3(d))
defines nonclinical laboratory studies as “in vivo or in vitro experiments in which test articles
are studied prospectively in test systems under laboratory conditions to determine their safety.
The term does not include studies using human subjects or clinical studies or field trials in

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animals. The term does not include basic exploratory studies carried out to determine whether a
test article has any potential utility….”
The requirements of part 58 apply to nonclinical studies submitted to support safety findings,
including nonclinical pharmacogenomic studies intended to support regulatory decision making.
If full compliance with 21 CFR Part 58 cannot be met, a sponsor must clearly indicate in the
study report the areas in which such data do not comply with Part 58 (§§ 312.23(a)(8)(iii) and
314.50(d)(2)(v)). Any studies eligible to be submitted in an abbreviated report, synopsis, or
VGDS under the algorithms discussed above do not fall under part 58.
The FDA recognizes that it may not be feasible to conduct separate, long-term, non-GLP
preclinical studies. For this reason, FDA encourages sampling of tissues from GLP studies for
investigational purposes. Removal of tissue samples and the reason for removal (e.g.,
exploratory, mechanistic study, tissue banking) should be specified in the protocol. Removal of
specimens for investigational purposes from a study does not invalidate the GLP status of the
main toxicology study, if otherwise acceptable. If the tissue samples are subsequently analyzed,
the results should be reported to the NDA as a synopsis. The FDA would also be interested in
receiving these data in a VGDS. If findings from these studies are considered by the sponsor to
be relevant to the safety of the compound under study (e.g., related to a known valid biomarker),
the findings must be reported to the application, as is necessary for any other relevant nonclinical
study findings 312.23(a)(8), 312.32(c)(1)(i)(B), 314.50(d)(2)).
E.

Submission of Voluntary Genomic Data from Application-Independent
Research

The FDA will also accept pharmacogenomic data from investigators who may not have an active
IND, NDA, or BLA , but who wish to provide the information voluntarily to FDA, according to
the process described in Section VI of this guidance.
We recommend that all VGDSs be prominently marked as VGDS, or VOLUNTARY
SUBMISSIONS, on the cover letter that accompanies the submission (see Appendix E).

V.

FORMAT AND CONTENT OF A VGDS

The FDA invites submission of exploratory pharmacogenomic data on drugs or candidate drugs
whether or not the molecules are currently the subject of an active IND, NDA, or BLA.
Exploratory genomic data may result from, for example, microarray expression profiling
experiments, genotyping or single-nucleotide polymorphism (SNP) profiling experiments, or
from other studies using evolving methodologies that are intended to facilitate global analysis of
gene functions, but not specific claims pertaining to drug dosing, safety assessments, or
effectiveness evaluations. Currently, consensus standards do not exist for presenting and
exchanging genomic data, although such standards are evolving. Therefore, this guidance does
not recommend a specific data format for the VGDS.

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We recommend that, to achieve the goals of the VGDS process as delineated in Section III(C),
the content of a VGDS, and the level of detail, be sufficient for the Agency to interpret the
information and independently analyze the data, verify results, and explore possible genotypephenotype correlations across studies. We do not, however, want the submission of a VGDS to
be overly burdensome and time-consuming for sponsors. Therefore, VGDS could be submitted
in a number of forms:
•

As an article submitted to a peer-reviewed scientific journal with raw or processed data
submitted electronically

•

As an evolving public standard for specific types of experiments, such as the Minimum
Information About a Microarray Experiment (MIAME) standard for microarray expression data.7
Using an approach similar in content to MIAME one can format a VGDS containing genotyping
or other genomic data derived from technology platforms other than nucleic acid hybridization
arrays.

•

As a full report on a gene expression microarray experiment, the content could contain the
following analytical, preclinical and/or clinical information, for example:
– Title page
– Table of contents
– Background and scientific rationale
– Primary and secondary study goals
– Synopses and summary of findings
– Study design and sample collection
– Array design and description
- Sample processing and preparation
- Demonstration of quality of RNA or DNA
- Hybridization procedures and parameters
- Measures of performance of hybridization such as spike-in control
- Measurements and quantification
- Normalization controls
- Number of repeats (array hybridized), number of biological assays performed
– Data Analysis
- Statistical analysis
- Bioinformatics tools and software used. Source of gene annotation
– Results and conclusions, including, for example, data visualization (e.g., scatter plots,
principle component analysis (PCA), hierarchical clustering (heat maps)), correlation
between expression profiles and outcomes, and appropriate information about
relevant co-factors
– References

•

Additional Study Information related to mircroarray studies might include the following:
– Confirmation of SNP analysis by sequencing or other assays

7

Brazma, A., et al., Nature Genetics, 29, 365-371, 2001 and http://www.mged.org/workgroups/miame.html.

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- Confirmation of gene expression by other conventional assays (e.g., Northern blot,
RT-PCR (real time polymerase chain reaction)). As much as possible, all genes of
importance should be confirmed with secondary assays. However, if the genomic
profile is of importance, it may be appropriate to sample a selected subpopulation of
affected genes
- Alternative approaches that examine endpoints other than gene expression changes
may also be appropriate under certain circumstances (e.g., immunohistochemistry
or Western blot, if reagents available).

VI.

PROCESS FOR SUBMITTING PHARMACOGENOMIC DATA

Using the decision trees (see Appendices A-C), sponsors should submit genomic data according
to the following recommendations.
•
•

VII.

For required submissions, complete reports, abbreviated reports, or synopses of
pharmacogenomic studies should be submitted to INDs, NDAs, or BLAs in the usual
manner.
For candidate drugs or stand alone voluntary submissions (submissions not related to any
application), sponsors should submit the package clearly labeled as VOLUNTARY
GENOMIC DATA SUBMISSION (VGDS). A voluntary submission cover sheet that
can be used is included in Appendix E. For VGDSs related to an existing IND, NDA, or
BLA, please include the reference number on the voluntary submission cover sheet.

AGENCY REVIEW OF VOLUNTARY GENOMIC DATA SUBMISSIONS

The FDA has received many questions about the use of pharmacogenomic data in the application
review process. Questions reflect the concern that the Agency will raise new questions and
require additional data based on findings from exploratory pharmacogenomic studies, that new
studies will be required or suggested based on preliminary human pharmacogenomic data, that
indicated populations will be narrowed or restricted based on the pharmacogenomic results in
subpopulations, or that new studies in subpopulations will be required after retrospective analysis
suggests differential responses based on pharmacogenomic subgrouping. There is also concern
about the availability of staff who are experts in interpretation of such data.
The FDA will not use genomic information submitted through the voluntary process for
regulatory decision making on INDs, BLAs, or NDAs.
VGDSs will be reviewed by the Interdisciplinary Pharmacogenomic Review Group (IPRG). The
review process is intended to ensure that scientific staff experienced in the evaluation of
genomics studies participate first-hand in analysis and review of the data. Any data evaluation
will be conducted for scientific and informational purposes — not for regulatory decision
making. If additional information becomes available after a sponsor submits a VGDS that
triggers the submission requirements under §§ 312, 314, or 601, the sponsor must resubmit the

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data to the investigational or marketing application and should follow the appropriate algorithm
described in this guidance for a required submission. Also, a review division may consult the
IPRG when pharmacogenomic data are submitted as part of an IND, NDA, or BLA.
The animal and in vitro toxicology database needed to support human trials at various stages of
the IND process and to support marketing of short- or long-term use drugs is well established.
Any proposals for the substitution or addition of new animal genomic safety tests will ordinarily
be the product of a public process involving the international scientific and drug development
communities. If FDA becomes aware that a particular pharmacogenomic test has taken on great
significance based upon cumulative experience (e.g., from evaluating results across submissions,
and/or obtaining input from Advisory Committees), the Agency will notify sponsors about its
findings.
Currently, as discussed above, only a few pharmacogenetic tests for certain drug metabolizing
enzymes are considered known valid biomarkers in humans. Considerable concern has been
expressed about how FDA will evaluate newer types of pharmacogenomic data (e.g., results that
may predict increased risk of adverse events, or point to an enhanced probability of effectiveness
response). The FDA has considerable experience dealing with these issues in other contexts.
Examples of how pharmacogenomic studies fit into this experience include the following.
•

Descriptions of drug metabolizing phenotypes and discussion of their effects on dosing
are common in drug labels. Extrapolation of this information to pharmacogenetic testing
is straightforward.

•

There are many conditions or co-factors that may increase an individual’s susceptibility
to an adverse event (e.g., co-morbid conditions, metabolic susceptibilities such as hepatic
failure, or concomitant drug therapies) or the probability of a beneficial response.

The FDA’s usual approach in such cases has been to request that information be added to the
drug labeling that describes the possible interaction and relevant co-factors and advises on
precautions. If a sponsor discovers a new pharmacogenomic test that could possibly distinguish
patients at greater risk for a serious adverse event, it is likely that both the sponsor and the
Agency would have great interest in exploring the correlation in the appropriate populations.
However, if the sponsor also moved forward on developing the drug in the overall indicated
population, FDA would evaluate the safety database on its merits. If the sponsor decided to
develop the drug solely in populations from which certain patients were excluded based on
pharmacogenomic testing, FDA would recommend co-development of the pharmacogenomic
test (as a diagnostic) and the drug because FDA would be unable to approve a drug for which the
risk or benefit was predicated on a pharmacogenomic test that was unavailable.
It is most likely that, in the near future, pharmacogenomic biomarkers that predict drug toxicity
will be identified and developed on a path parallel with overall drug development. In other
words, a drug would be developed in a conventional manner with a parallel effort to identify
appropriate predictors of toxicity. If the drug’s risk-benefit profile were acceptable in the entire
target population, the drug could be approved prior to the completion of efforts to refine and
develop the relevant pharmacogenomic tests. When and if a test's predictive values were to be

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established and the test were to become commercially available (either as an approved device or
as a service), the drug label could be changed to reflect the data.
•

The FDA has similar experience with tests used to target populations likely to respond to
therapy.

Several decades ago, broad indications for use were described in labels. Over time, as more
exact diagnoses were developed, narrower indications were sought by sponsors, based on the
clinical trials conducted. A similar evolution occurred in the field of anti-HIV therapies as drug
resistance testing became available. We encourage sponsors to continue to develop
pharmacogenomic tests that are predictive of subpopulations with enhanced response to therapy.
However, if overall drug development is pursued in the larger population, the effectiveness and
risk-benefit will be evaluated in that population, and approval decisions will be based on the
overall database.
Much of the concern about FDA actions in this area is based on the perception that
pharmacogenomic testing is likely to give definitive answers about the probability of safety and
effectiveness in subpopulations. Such specificity may occur occasionally (e.g., where a product
is designed to inhibit a specific molecular target), and in such cases, rapid development of a
diagnostic test is highly encouraged. However, this is unlikely to be the ordinary case. In most
instances, a genotype or particular gene expression profile is likely to be one of a number of
factors that affects the probability of an adverse event or a favorable response. For this reason,
pharmacogenomic biomarkers can ordinarily be handled like other non-genomic predictive
markers in the clinical arena.

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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.8
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 wellestablished 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.

8

Biomarkers Definitions Working Group, "Biomarkers and Surrogate Endpoints: Preferred Definitions and
Conceptual Framework," Clinical Pharm. & Therapeutics, vol. 69, N. 3, March 2001.

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– 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 FDA.

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APPENDIX 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
1 or 2, below?

Full report to IND

N
Y
Meets
3, below?

Abbreviated report to IND

N
No required submission needed; VGDS encouraged

Pharmacogenomic data must be submitted to the IND under § 312.23 if ANY of the following apply:

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Contains Nonbinding Recommendations
1.

The test results are used for making decisions pertaining to a specific clinical trial, or in an 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, for example, 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 required, 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 singlenucleotide polymorphism (SNP) analysis of trial participants.

5.

Information consists of results from test systems where the validity of the biomarker is not established.

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Contains Nonbinding Recommendations

APPENDIX 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

1.

The sponsor will use the test results in the drug labeling 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

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Contains Nonbinding Recommendations
NDA or BLA. If the pharmacogenomic test is already approved by 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.

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APPENDIX C: SUBMISSION OF PHARMACOGENOMIC (PG) DATA TO AN
APPROVED NDA, BLA, OR SUPPLEMENT

Animal or human PG study results

Y
Known or
probable valid
biomarkers?

Abbreviated report or synopsis

N
No required submission needed; VGDS encouraged

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APPENDIX D: QUICK REFERENCE ON PHARMACOGENOMIC SUBMISSIONS

Submitting
data to an:

Known
Valid
Biomarker

Probable
Valid
Biomarker

Exploratory or
Research
Pharmacogenomic Data

IND

New (Unapproved)
NDA, BLA, or
Supplement

Must be submitted,
pursuant to
21 CFR 312.23 (a)
(8), (9), (10) (iv) or
(11).

Must be submitted,
pursuant to
21 CFR 314.50 and
601.2. See section IV.B.
of the guidance.

Must be submitted pursuant
to 21 CFR 314.81 in annual
report and should be
submitted pursuant to
§ 601.12 as synopses or
abbreviated reports.

Does not need to be
submitted.9

The FDA recommends
submission, using
algorithm in section
IV.B. of the guidance.

Must be submitted pursuant
to 21 CFR 314.81 in annual
report and should be
submitted pursuant to
§ 601.12 as synopses or
abbreviated reports.

The FDA recommends
submission, using
algorithm in section
IV.B. of the guidance.

The FDA welcomes
voluntary submission of
such data in a VGDS.

The FDA welcomes
voluntary submission
of such data in a
VGDS.

The FDA welcomes
voluntary submission
of such data in a
VGDS.

The FDA welcomes
voluntary submission of
such data in a VGDS.

9

Previously Approved NDA
or BLA

Except if used in human safety studies.

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APPENDIX E: VOLUNTARY SUBMISSION COVER SHEET
Send all CDER voluntary genomic data submissions to the following address accompanied by this
coversheet:
FDA/CDER
Central Document Room (CDR)
5901-B Ammendale Road
Beltswille, MD 20705-1266

Attention!
This is a

Voluntary
Genomic Data Submission
Application number ________ (leave blank if this is the first submission for a stand-alone VGDS)

_______Initial Submission
_______Subsequent Submission

Please route directly to the IPRG (HFD-850)
After processing in the CDR!

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