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Genomics
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Frequently Asked Questions
Voluntary Exploratory Data Submissions (VXDS and X=exploratory) program
The following frequently asked questions refer to Voluntary Exploratory Data Submissions (VXDS and X=exploratory) program expanded from the Voluntary genomic data submission (VGDS) program
What are the steps to submit Voluntary Exploratory Data Submission?
- The initial step is to contact either the Chair or Executive Secretary of the Interdisciplinary Pharmacogenomics Review Group (IPRG) to discuss the scope of the proposed VXDS.
- A VXDS request would then be submitted 6 to 8 weeks prior to the proposed date for the meeting.
- The genomic data for the meeting would be submitted at least four weeks prior to the meeting.
- Additional details of the submission steps are in the MaPPs and Best Practices for Effective and Productive VXDS Meetings.
Who participates in the review of VXDS data?
Members of the IPRG. Additional resources are requested on an as needed basis from individual reviewers (Center Experts) that are experts in specific fields (i.e. therapeutic areas). These experts are not involved in the review of data from required submissions that are associated with voluntarily submitted information.
How is the scientific nature of a VXDS discussion structured?
The IPRG review of a VXDS is a scientific discussion in parallel to a regulatory context.
How will confidentiality of the VXDS be ensured by the Agency?
All VXDS data will be protected from disclosure to the extent allowed by existing laws and regulations, and consistent with our policies for disclosure of other data submitted to INDs, new drug applications (NDAs), and biologic license applications (BLAs). Data that are submitted to existing INDs, NDAs, or BLAs will receive the number of their existing application. VXDS data that are not part of an existing submission will receive a new IND number. All VXDS data will be routed directly to the IPRG, not the review division, and will stored on a secured, separate server.
How will the VXDS data be distributed within the Agency?
All VXDS data will be distributed only within the IPRG, unless there is prior agreement with the sponsor.
How will the VXDS data be stored within the Agency?
All VXDS data will be stored on a separate secure server that is accessible to members of the IPRG only. It will not be distributed outside the IPRG without the prior agreement of the sponsor.
What are some of the incentives to sponsors to submit VXDS?
- Provides opportunity to have informal meeting with FDA pharmacogenomics experts
- Receive and benefit from informal peer-review feedback on pharmacogenomics issues and/or questions.
- Gain insight into current FDA thinking about pharmacogenomics that may assist in reach strategic decisions.
- Familiarize FDA with pharmacogenomics experiments, data analysis and interpretation approaches.
- Paves the way for time- and cost-savings by familiarizing FDA with pharmacogenomics and avoiding future delays in review.
- Impact FDA thinking and help build consensus around pharmacogenomics standards, policies and guidances.
What activities does the IPRG engage in?
- Reviews and evaluates VXDSs.
- Meets with sponsors upon request before or after submitting a VXDS.
- Consults upon request with review staff on required submissions containing genomic data.
- Integrates pharmacogenomics into the regulatory review process and helps develop future guidance and review standards.
- Harmonizes review practices and quality review systems for genomic data submissions.
- Coordinates among disciplines and organizations in FDA, in particular CBER, CDER, Office of Combination Products (OCP), CDRH and NCTR, to assure the efficient, accurate, and transparent review of genomic data.
- Coordinates public discussions and agendas for advisory committee meetings with regard to "lessons learned" from Genomic Data Submission review
- Defines key issues to advance the use of rational pharmacogenomic principles in drug development, in particular issues pertaining to the regulatory review process.
- Facilitates FDA internal education regarding pharmacogenomic data, including seminars and printed materials.
What are the submission format steps followed for hybridization data?
No specific format is required. A summary of the results should be discussed when the VXDS meeting is requested. Raw hybridization data, such as .cel files, are extremely useful for VXDS review in order to match the analytical process followed by the sponsor before the formal VXDS meeting is scheduled.
Is it correct to assume that genetic data are to be kept as long as any other clinical data collected in a trial?
Yes.
We have genomic data related to a previous clinical submission that was not approved. Can we submit it as a VXDS?
Yes.
Can data on genomic biomarker validation be submitted as a VXDS?
Yes. This is an example of a VXDS leading to a scientific discussion about new genomic biomarkers. Alternatively submit via biomarker qualification process.
Biomarker Qualification Process
The following frequently asked questions refer to biomarker qualification discussion in the “Guidance for industry-Pharmacogenomics Data Submission” http://www.fda.gov/cder/guidance/6400fnl.pdf
Will the FDA be issuing specific guidances on the qualification and use of genomic biomarkers?
Guidance on the validation and use of genomic biomarker is planned, but not yet initiated.
We have new genomic data for a study on a drug that was previously approved. Should we submit it through a VXDS or Biomarker Qualification process?
If the data is a regulatory follow-up of a clinical submission, it needs to be submitted within the original regulatory requirements.
If the data was obtained after completing or outside of the regulatory requirements, the exploratory biomarker data are submitted via VXDS process. Data for biomarker qualification should be submitted through the biomarker qualification process. Data for co-development of a test and a drug should follow recommendations in the co-development concept paper http://www.fda.gov/Cder/genomics/pharmacoconceptfn.pdf
Question on Biomarker Terminology and Qualification
Since the Guidance for Industry Pharmacogenomics Data Submissions and its Appendix (http://www.fda.gov/cder/guidance/6400fnl.pdf) was published in final form in March, 2005, the concept of biological validation for new biomarkers has evolved from exploratory, probable valid, and known valid categorizations in favor of the biological qualification concept as a context dependent, graded evidentiary process linking a biomarker to a specific purpose.
When the qualification of biomarkers that would be appropriate to help assess drug safety for regulatory decision making purposes involves establishing a "fit-for-purpose" based evidentiary threshold, how should industry and regulatory scientists assess that this level of utility has been achieved? And what is the need to report data for either "exploratory" or "fit-for-purpose qualified" safety biomarkers that may be measured on GLP animal toxicology studies?
Response
The Guidance identified three categories of biomarkers: exploratory, probable valid, and known valid. The Guidance noted that the field of genomics was in early developmental stages but rapidly evolving. The Guidance also noted that the distinction between what tests are appropriate for regulatory decision-making and those that are not will change over time as the science evolves.
Recently, a new framework for a performance-and purpose-based classification of biomarkers has been discussed in the scientific literature, i.e.,"fit-for-purpose" (e.g., see Lee et al, Pharmaceutical Res1-17, 2006 (http://www.questpharm.com/PDF/LeePharmaRes2006,23,2,312.pdf). For biomarkers that are deemed fit for the purpose of detecting toxicity and monitoring drug safety and therefore qualified for use in a regulatory decision-making context, the underlying science must be sufficiently rigorous to match the critical level of evidence and performance that would be needed. Sufficient qualification data must exist to define the fitness of a biomarker for a regulatory purpose involving safety evaluation and toxicity detection.
The concept of fit-for-purpose is consistent with the discussion of biomarkers in the Guidance and the evolving nature of biomarker qualification further underscores that a significant effort is necessary to cross a scientifically credible threshold from an unqualified or exploratory biomarker, which would not be appropriate for a regulatory data submission filing, to a qualified safety biomarker appropriate for regulatory decision-making. For any exploratory safety biomarker to be considered newly qualified as fit-for-purpose the qualification process is usually incremental. Any additional data required to support qualification for regulatory use will be expected to depend on what data may already be publicly available, may lie within regulatory repositories, with individual sponsors, or available from consortia and institutions. Sponsors and regulatory authorities share a responsibility for acknowledging when new safety biomarkers are appropriately qualified for regulatory decision making.
Question on Reassessment of Exploratory Biomarker Data
A sponsor may generate exploratory biomarker data on samples from a GLP animal toxicology study and, in accordance with the Guidance document, will not need to submit the data to an IND but could choose to submit the data as a Voluntary Submission. However, over time the exploratory biomarker may evolve to a qualified safety biomarker fit for regulatory decision making. Is it necessary to search out, reanalyze, reassess, and submit to an active IND or NDA exploratory biomarker data on endpoints that may later become qualified, if subsequently conducted definitive drug development studies of longer duration or if safety studies in the clinic have been completed and have satisfactorily addressed any potential such human safety concerns?
Response
Industry has raised some concerns over the need to continually reanalyze biomarker data from their studies as new information becomes available. Specifically, the concern was raised based on the following excerpt from the Guidance.
"If additional information becomes available after a sponsor submits a VXDS that triggers the submission requirements under §§ 312, 314, or 601, the sponsor must resubmit the data to the investigational or marketing application and should follow the appropriate algorithm described in this guidance for a required submission."
This statement referring to relevant sections of the Code of Federal Regulations (CFR) discusses the procedural nature of a reporting requirement, if one exists; that is, submission of a VXDS is not sufficient to meet the reporting requirements to the Agency. To fulfill a reporting requirement, a sponsor will need to submit data on any qualified biomarkers that would be deemed "pertinent to safety", in accordance with those referenced sections of the CFR, to the IND or NDA in a reviewing division generated from animal toxicology studies that were used to support the safe conduct of upcoming clinical trials.
A decision by a sponsor to reanalyze and submit data from animal toxicology studies based on the availability of a newly qualified biomarker should be made in the context of other available nonclinical and clinical data. As an example, there is no general expectation that microarray data from the rat kidney would need to be reanalyzed and submitted to an IND or NDA if a renal safety biomarker were subsequently qualified, provided that the pivotal GLP toxicology studies that examined the potential for kidney toxicity have been adequately conducted, even if the samples for microarray were generated in that GLP toxicology study, or in a previously conducted shorter duration study. The circumstances driving decisions to reanalyze data will be highly context dependent, are expected rarely, and would be made on a case-by-case basis.
Pharmacogenomics Tests for Valid Biomarkers
The following frequently asked questions refer to Pharmacogenomics tests for valid biomarkers in the approved drug labels
Are there FDA approved PGx tests for screening valid biomarkers in FDA marketed drug labels?
The FDA marketed drug package/ label inserts in some instances depending on the context of use, provide information on availability of tests for screening valid biomarkers.Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels An example of FDA approved tests in drug labels includes:
- Invader® UGIlAl Molecular Assay can identify whether a patient has the genetic variant affecting the metabolism of Camptosar and thus would be at higher risk for developing severe neutropenia. The drug label says to consider lowering the starting dose of the Camptosar for those patients found to be high risk.
Are there Pharmacogenomic tests regulations for clinical use?
Pharmacogenomic tests for clinical use in general regulated by Clinical laboratory Improvement Amendments (CLIA) of 1988 or by FDA standards that qualify as devices as the case may be. Visit CDRH web site http://www.fda.gov/cdrh/ and CDRH guidance for PGx tests http://www.fda.gov/cdrh/oivd/guidance/1549.pdf. Note that the FDA clearance or approval is a completely different process than biomarker qualification.
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Date created: March 22, 2005, updated November 18, 2008 |
