April 15, 2005 (Vol. 25, No. 8)

Agency’s Guidance Now Final

The FDA announced the availability of its long-awaited pharmacogenomic data guidance on March 23 (70 FR 14698). The document, entitled Guidance for Industry: Pharmacogenomic Data Submissions (and referred to in this article as the Final Guidance), reflects the Agencys evaluation of comments received following its release of a draft version (referred to in this article as the Draft Guidance) on November 4, 2003, (68 FR 62461).

In its Notice announcing the Final Guidance, the Agency characterized the differences from the Draft Guidance as mainly clarifications of statements made in the earlier version, but it did highlight three noteworthy changes:

the replacement of Appendix D to the Draft Guidance (providing examples of pharmacogenomic data submissions) with an Attachment to the Final Guidance concurrently issued as a separate document so that additional examples can be added over time;

the addition of a new appendix E (providing a distinctive form cover sheet for voluntary submissions of pharmacogenomic data) to help ensure such submissions are routed to the Interdisciplinary Pharmacogenomics Review Group (IPRG) and not to a review section within a Center; and

the creation of internal agency procedures (again, as separate documents incorporated in the CDER and CBER policy and procedures manuals) to specifically address the procedure of submitting and reviewing voluntary genomic data submissions and the function and responsibilities of the Interdisciplinary Pharmacogenomics Review Group.

Closely Follows Draft Document

The Final Guidance closely adheres to the overall organization and content of the Draft Guidance. A line by line comparison between the two documents suggests that the changes made by the Agency in preparing the later version are more in the nature of clarifications than any outright reworking of the scope or structure of the earlier version.

Thus, for example, the Final Guidance reiterates that pharmacogenomic data must accompany investigational and marketing submissions when the data are used for decision making in the context of specific preclinical or clinical trials or to support scientific arguments to the Agency relating to issues of safety or effectiveness.

Unless the test results constitute a known, valid biomarker, in which case a summary will suffice, the sponsor shall submit a full report describing the test and the data obtained.

In the absence of any specific and comprehensive discussion of the public comments submitted regarding the Draft Guidance, the FDAs acknowledgement of and response to those comments might be gleaned from those clarifications.

Our earlier article regarding the Draft Guidance (see GEN, February 15, 2005, p. 18) summarized points raised in sometimes extensive evaluations of that document submitted to the public docket by several pharmaceutical and biotechnology companies. Key issues identified in those comments included:

the meaning and significance of a sponsors decision making or the FDAs regulatory decision making for purposes of identifying required submissions of pharmacogenomic data (e.g., several comments noted that pharmacogenomic data may be used through the discovery process to prioritize drug candidates without subsequently serving to address questions of safety or efficacy during the development testing of specific candidates);

the process by which a pharmacogenomic test would become recognized and accepted for regulatory decision making as a known valid biomarker;

confidentiality and control of intellectual property in the voluntary submission of pharmacogenomic data; and

whether submission of pharmacogenomic data could be in conflict with state and federal medical and genetic privacy legislation.

The first and second of these key issues are addressed in the Final Guidance, the first explicitly and the second implicitly. There are no observable changes in the Final Guidance that appear to respond to the third and fourth issues, although the new IPRG internal procedures do address the third issue.


The Final Guidance introduces explanations of the regulatory decision making and decision making by the sponsor phrases. As used in the Final Guidance, regulatory decision making 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 and may occur throughout the investigational stages of product development, during premarket review, and during postmarket regulation.

Decision making by the sponsor means 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.

These explanations help clarify the point that a sponsor will be able to distinguish when its use of pharmacogenomic data may assume regulatory significance, although the full measure of that significance may not be as readily apparent.

Certain test results assume greater regulatory significance to the extent to which they constitute a known, valid biomarker, making the identification of such markers a key element in the expanded use of pharmacogenomic data in regulatory decision making.

Like its antecedent, the Final Guidance expresses the Agencys expectation that biomarkers will achieve known, valid status through the ongoing examination of and extrapolation from Voluntary Genomic Data Submissions (VGDSs).

However, to bolster industry commitment to such a process, the Final Guidance explains that voluntary submissions can benefit product sponsors as well, and it notes, in particular, that [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.

The Final Guidance also encourages investigational sampling of tissues from GLP studies and submission of voluntary genomic data from application-independent research to generate a greater resource of historical information from which known, valid biomarkers may emerge from currently observational or exploratory ones.

Reviewing the VGDSs

The details of the process of biomarker vetting are not offered in the Final Guidance, but do appear in the internal procedures drafted for the management and operation of the IPRG.

These procedures describe in summary fashion how the IPRG will review VGDSs and, with consent of the sponsor and redaction of confidential information, how it may convene an Advisory Subcommittee meeting from time to time to discuss, with public input, whether enough has become known about a test to warrant designation as a known, valid biomarker.

The IPRG is specifically charged with evaluating each VGDS and providing a report to the submitting sponsor regarding its interpretation of the test data.

In the event the IPRG independently concludes that the VGDS data are applicable to the regulatory review of a drug that is the subject of an investigational or marketing application, it will notify the sponsor and ask that the information be submitted to the relevant application as a required submission.

As it has throughout its public exploration of its thinking regarding the utility of pharmacogenomics, the Agency has stressed that its consideration of test data is a part of a larger effort to support progress in this field.

For example, the FDAs Final Guidance Notice also reports that it is working toward the release of a Concept Paper on Pharmacogenomic Drug Diagnostic Co-Development as a first step in the creation of a draft guidance on that subject.

In fact, the Final Guidance begins by reforming the focus of the intent of facilitating scientific progress and the use of pharmacogenomic data expressed in the earlier version from regulatory decisions to drug development.

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