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Questions and answers about the Pilot Process for Biomarker Qualification at the FDA
Drug Discovery Today: Technologies
Vol. 4, No. 1 2007
Editors-in-Chief Kelvin Lam – Harvard Stem Cell Institute, Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Critical path
Questions and answers about the Pilot Process for Biomarker Qualification at the FDA Federico M. Goodsaid*, Felix W. Frueh Genomics Group, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA
The FDA has developed a Pilot Process for Biomarker Qualification. Initial experience with this process has underscored the care that a long-term approach to
Section Editor: Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
biomarker qualification independently of development for specific drugs should have in the assembly of external industry consortia as well as the internal regulatory organization for these qualification efforts. There are complex scientific and clinical issues associated with these qualifications, and it is paramount that the expertise needed for their review be identified so that a comprehensive consensus may be reached at the end of this process. Several frequently asked questions associated with this process are presented in this paper, as well as answers reflecting the Agency’s current thinking about this process. Introduction There is a wide variety of genomic tests both under development as well as currently marketed. However, the uptake of these tests into routine clinical practice has been slow. Hesitation in the application of these tests is often associated with a lack of clarity in the context and supporting evidence for their application [1]. Pharmacogenomic/genetic tests can be integrated into clinical practice when we know the context
*Corresponding author: F.M. Goodsaid ([email protected]) 1740-6749/$ .Published by Elsevier Ltd.
DOI: 10.1016/j.ddtec.2007.10.005
in which we are measuring the genomic/genetic marker and the evidence supporting this measurement. The path from an exploratory biomarker to a biomarker qualified for clinical use independently of specific drugs can be a long and tortuous one. Application of these biomarkers requires an objective record for their nonclinical or clinical context and supporting qualification evidence. Information from the development of exploratory biomarkers in pharmacogenomics has been shared between the pharmaceutical industry and the FDA through Voluntary eXploratory Data Submissions (VXDS). For example, submissions of microarray data have allowed reviewers at the FDA to share with scientists in the pharmaceutical industry study designs, sample isolation and storage protocols, technology platforms, analysis algorithms, biological pathway interpretation, and electronic data submission formats. This experience has been valuable in training our reviewers for the analysis and interpretation of genomic data. We think we know what exploratory biomarkers are. We may also know well what valid biomarkers can look like. Sources of data supporting the application of pharmacogenomic biomarkers in clinical contexts are available in drug labels. The FDA has published on its website (http://www.fda. gov/cder/genomics/genomic_biomarkers_table.htm) a table summarizing pharmacogenomic biomarkers in the context 9
Drug Discovery Today: Technologies | Critical path
of drug labels. This table is a useful model to showcase the concepts of biomarker context and biomarker qualification supporting data. The table shows language in the drug label descriptive of how and when a biomarker is to be used, and linkage between testing for this biomarker and therapeutic decision-making. For example, the table differentiates on a scale of 1–3 between therapies for which testing is required (such as Herceptin, which received a ‘1’) and most of the others (which received a ‘3’) for which information from this testing is considered useful but not required in therapeutic decisions. A qualification in context for the FDA may or may not require the same dataset as one for a broader clinical application beyond drug approval [2]. VXDS submissions have stressed the need for a regulatory path from exploratory biomarkers to biomarkers qualified for a specific context. Such a path is currently being tested at the FDA through a Pilot Process for Biomarker Qualification [3]. This Pilot Process is focused on the specific needs of the regulatory environment to ensure scientific accurate and clinically (or pre-clinically) useful decision-making. There are a number of questions and answers with which we can outline what the Pilot Process for Biomarker Qualification is and what we will need to successfully apply it.
Q&A about the Pilot Process for Biomarker Qualification at CDER What is a 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. (http://www.fda.gov/cder/guidance/6400fnl.pdf) Other definitions for valid biomarkers have been proposed previously, but the qualification of a biomarker requires the addition of a context of use (fit for purpose) which specifies not only how a biomarker will be applied but also the studies and data associated with its qualification. Does the application of new biomarkers increase the cost of drug development? Biomarkers selected for qualification should reduce time, development cost or adverse events in drug development. The initial impact of the application of a new biomarker on the cost of a drug development process may very well be negative. The impact of biomarkers on drug development may be expected to become clear over several development programs. In the Pilot Process for Biomarker Qualification, we are focusing on biomarkers that may be expected to have an impact on drug development and regulatory review. Will regulators know what these new biomarkers are for? An integral goal of the qualification process will be a comprehensive training of reviewers on the context, qualification data and application of qualified biomarkers. This is an extremely important goal in biomarker qualification, addres10
www.drugdiscoverytoday.com
Vol. 4, No. 1 2007
sing common concerns that reviewers will overinterpret or misinterpret biomarker data. An accurate definition of biomarker context will contribute to both a robust qualification process as well as to their eventual application in regulatory review. Why should we replace biomarkers for which we have massive databases to support control ranges? If a biomarker is available currently to aid in drug development, it serves as a useful reference in the development of new biomarkers. New biomarkers make sense when they provide better or different information than the biomarkers in current use. Their use may have analytical, nonclinical or clinical advantages, or may simply expand the information available from current biomarkers. What if the new biomarker is ‘too’ sensitive? If a biomarker can be qualified to show that it has a specificity comparable to a currently available biomarker, it is also possible to determine how its sensitivity compares with that of current biomarkers. It is possible that a new biomarker will provide either better diagnostic sensitivity or/and the potential for a predictive application. What standard should I use to qualify a new biomarker? We should use an accurate measurement of the outcome for which we are trying to develop new biomarkers. Histopathology data will often be a valuable standard in the development of biomarkers for preclinical drug safety assessment. Clinical qualification will depend on the context of use for the new biomarker. Biomarkers which help guide therapeutic decisions need to be qualified around this decision-making process. Those which are being developed as improved diagnostics need to be compared against the diagnostic standard in current use. Must test qualification precede biomarker qualification? Biomarker qualification precedes test qualification. Analytical validation is an integral part of biomarker qualification, but there is an excellent chance that if it is a novel biomarker there will be no off-the-shelf tests available for it. An aggressive effort for biomarker qualification cannot always depend on commercially available tests, since these may not be developed before an accurate estimate can be made for their market. Does the quality of data for qualification correspond to impact metric of publications related to biomarker? Proprietary data on key biomarkers in drug development may not reach publication until after data suitable for their qualification are available. Successful biomarker contexts are related to their impact on better, faster, cheaper drug development and safer drugs. Could biomarkers be ‘voted’ into qualification independently of whether sufficient data support their qualification? Biomarkers are qualified on the basis of the data that support their use in the context in which they are qualified. Biomarker contexts are closely associated with the regulatory agencies that use them. This context-specific qualification will be difficult if it
Vol. 4, No. 1 2007
is isolated from a rigorous analysis of scientific and clinical qualification data. Are evidentiary standards for biomarker qualification different for preclinical and clinical biomarkers? Evidentiary standards are context-driven. Evidence for biomarker qualification is associated, for example, with whether a biomarker is predictive, diagnostic, or mechanistic. Are predictive preclinical drug safety biomarkers the only ones worth qualifying? Newly qualified diagnostic and mechanistic preclinical drug safety biomarkers have immediate impact on drug development. However, any new biomarker with a positive impact in drug development and regulatory review is a good candidate fro qualification. Is the cost of biomarker qualification always carried by single pharmaceutical companies? Organizations such as the Predictive Safety Testing Consortium (PSTC) have developed the legal framework needed share the cost of qualification and to protect intellectual property associated with biomarker qualification. Pre-competitive sharing of qualification data is a cost-effective process with which to quickly reach a data threshold for qualification. Does biomarker qualification always require a public process? Qualification requires data generated by companies in industries regulated by specific regulatory agencies. Proprietary qualification data can be shared between companies in regulated industries and their regulatory agencies. These data may or may not be published. Could proposals for biomarker qualification originate from outside the pharmaceutical industry? Yes. The initial proposal for qualification consists of a two-page letter outlining the definition, context and supporting data for the proposed biomarker qualification. Proposals can be received from
Drug Discovery Today: Technologies | Critical path
Industry, Academic, Government or other scientists and clinicians. What are the key steps in the submission of qualification proposals for the Biomarker Qualification Pilot Process? In addition to the initial letter, other steps include: (1) Full submission of qualification data for review by the Biomarker Qualification review Team (BQRT) at the FDA. (2) VXDS meeting to go over the qualification data and to identify potential information gaps before a full review can be completed for the qualification package. (3) Review drafted by BQRT. (4) Internal review at FDA. (5) Communication of decision to sponsor.
Conclusion The need for an accurate, comprehensive and efficient process for biomarker qualification is closely linked with our ability to quickly integrate new biomarkers in drug development and regulatory review. The Biomarker Qualification Pilot Process at the FDA is testing the scientific, clinical and regulatory components for a biomarker qualification process. Experience gained with this currently ongoing pilot process will be useful in the development of a formal regulatory process for biomarker qualification.
References 1 2 3
Goodsaid, F. and Frueh, F. (2006) Process map proposal for the validation of genomic biomarkers. Pharmacogenomics 7, 773–782 Goodsaid, F. and Frueh, F.W. (2007) Implementing the U.S. FDA guidance on pharmacogenomic data submissions. Environ. Mol. Mutagen. 48, 354–358 Goodsaid, F. and Frueh, F. (2007) Biomarker qualification pilot process at the US Food and Drug Administration. AAPS J. 9, E105–E108
www.drugdiscoverytoday.com
11
Vol. 4, No. 1 2007
Editors-in-Chief Kelvin Lam – Harvard Stem Cell Institute, Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Critical path
Questions and answers about the Pilot Process for Biomarker Qualification at the FDA Federico M. Goodsaid*, Felix W. Frueh Genomics Group, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA
The FDA has developed a Pilot Process for Biomarker Qualification. Initial experience with this process has underscored the care that a long-term approach to
Section Editor: Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
biomarker qualification independently of development for specific drugs should have in the assembly of external industry consortia as well as the internal regulatory organization for these qualification efforts. There are complex scientific and clinical issues associated with these qualifications, and it is paramount that the expertise needed for their review be identified so that a comprehensive consensus may be reached at the end of this process. Several frequently asked questions associated with this process are presented in this paper, as well as answers reflecting the Agency’s current thinking about this process. Introduction There is a wide variety of genomic tests both under development as well as currently marketed. However, the uptake of these tests into routine clinical practice has been slow. Hesitation in the application of these tests is often associated with a lack of clarity in the context and supporting evidence for their application [1]. Pharmacogenomic/genetic tests can be integrated into clinical practice when we know the context
*Corresponding author: F.M. Goodsaid ([email protected]) 1740-6749/$ .Published by Elsevier Ltd.
DOI: 10.1016/j.ddtec.2007.10.005
in which we are measuring the genomic/genetic marker and the evidence supporting this measurement. The path from an exploratory biomarker to a biomarker qualified for clinical use independently of specific drugs can be a long and tortuous one. Application of these biomarkers requires an objective record for their nonclinical or clinical context and supporting qualification evidence. Information from the development of exploratory biomarkers in pharmacogenomics has been shared between the pharmaceutical industry and the FDA through Voluntary eXploratory Data Submissions (VXDS). For example, submissions of microarray data have allowed reviewers at the FDA to share with scientists in the pharmaceutical industry study designs, sample isolation and storage protocols, technology platforms, analysis algorithms, biological pathway interpretation, and electronic data submission formats. This experience has been valuable in training our reviewers for the analysis and interpretation of genomic data. We think we know what exploratory biomarkers are. We may also know well what valid biomarkers can look like. Sources of data supporting the application of pharmacogenomic biomarkers in clinical contexts are available in drug labels. The FDA has published on its website (http://www.fda. gov/cder/genomics/genomic_biomarkers_table.htm) a table summarizing pharmacogenomic biomarkers in the context 9
Drug Discovery Today: Technologies | Critical path
of drug labels. This table is a useful model to showcase the concepts of biomarker context and biomarker qualification supporting data. The table shows language in the drug label descriptive of how and when a biomarker is to be used, and linkage between testing for this biomarker and therapeutic decision-making. For example, the table differentiates on a scale of 1–3 between therapies for which testing is required (such as Herceptin, which received a ‘1’) and most of the others (which received a ‘3’) for which information from this testing is considered useful but not required in therapeutic decisions. A qualification in context for the FDA may or may not require the same dataset as one for a broader clinical application beyond drug approval [2]. VXDS submissions have stressed the need for a regulatory path from exploratory biomarkers to biomarkers qualified for a specific context. Such a path is currently being tested at the FDA through a Pilot Process for Biomarker Qualification [3]. This Pilot Process is focused on the specific needs of the regulatory environment to ensure scientific accurate and clinically (or pre-clinically) useful decision-making. There are a number of questions and answers with which we can outline what the Pilot Process for Biomarker Qualification is and what we will need to successfully apply it.
Q&A about the Pilot Process for Biomarker Qualification at CDER What is a 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. (http://www.fda.gov/cder/guidance/6400fnl.pdf) Other definitions for valid biomarkers have been proposed previously, but the qualification of a biomarker requires the addition of a context of use (fit for purpose) which specifies not only how a biomarker will be applied but also the studies and data associated with its qualification. Does the application of new biomarkers increase the cost of drug development? Biomarkers selected for qualification should reduce time, development cost or adverse events in drug development. The initial impact of the application of a new biomarker on the cost of a drug development process may very well be negative. The impact of biomarkers on drug development may be expected to become clear over several development programs. In the Pilot Process for Biomarker Qualification, we are focusing on biomarkers that may be expected to have an impact on drug development and regulatory review. Will regulators know what these new biomarkers are for? An integral goal of the qualification process will be a comprehensive training of reviewers on the context, qualification data and application of qualified biomarkers. This is an extremely important goal in biomarker qualification, addres10
www.drugdiscoverytoday.com
Vol. 4, No. 1 2007
sing common concerns that reviewers will overinterpret or misinterpret biomarker data. An accurate definition of biomarker context will contribute to both a robust qualification process as well as to their eventual application in regulatory review. Why should we replace biomarkers for which we have massive databases to support control ranges? If a biomarker is available currently to aid in drug development, it serves as a useful reference in the development of new biomarkers. New biomarkers make sense when they provide better or different information than the biomarkers in current use. Their use may have analytical, nonclinical or clinical advantages, or may simply expand the information available from current biomarkers. What if the new biomarker is ‘too’ sensitive? If a biomarker can be qualified to show that it has a specificity comparable to a currently available biomarker, it is also possible to determine how its sensitivity compares with that of current biomarkers. It is possible that a new biomarker will provide either better diagnostic sensitivity or/and the potential for a predictive application. What standard should I use to qualify a new biomarker? We should use an accurate measurement of the outcome for which we are trying to develop new biomarkers. Histopathology data will often be a valuable standard in the development of biomarkers for preclinical drug safety assessment. Clinical qualification will depend on the context of use for the new biomarker. Biomarkers which help guide therapeutic decisions need to be qualified around this decision-making process. Those which are being developed as improved diagnostics need to be compared against the diagnostic standard in current use. Must test qualification precede biomarker qualification? Biomarker qualification precedes test qualification. Analytical validation is an integral part of biomarker qualification, but there is an excellent chance that if it is a novel biomarker there will be no off-the-shelf tests available for it. An aggressive effort for biomarker qualification cannot always depend on commercially available tests, since these may not be developed before an accurate estimate can be made for their market. Does the quality of data for qualification correspond to impact metric of publications related to biomarker? Proprietary data on key biomarkers in drug development may not reach publication until after data suitable for their qualification are available. Successful biomarker contexts are related to their impact on better, faster, cheaper drug development and safer drugs. Could biomarkers be ‘voted’ into qualification independently of whether sufficient data support their qualification? Biomarkers are qualified on the basis of the data that support their use in the context in which they are qualified. Biomarker contexts are closely associated with the regulatory agencies that use them. This context-specific qualification will be difficult if it
Vol. 4, No. 1 2007
is isolated from a rigorous analysis of scientific and clinical qualification data. Are evidentiary standards for biomarker qualification different for preclinical and clinical biomarkers? Evidentiary standards are context-driven. Evidence for biomarker qualification is associated, for example, with whether a biomarker is predictive, diagnostic, or mechanistic. Are predictive preclinical drug safety biomarkers the only ones worth qualifying? Newly qualified diagnostic and mechanistic preclinical drug safety biomarkers have immediate impact on drug development. However, any new biomarker with a positive impact in drug development and regulatory review is a good candidate fro qualification. Is the cost of biomarker qualification always carried by single pharmaceutical companies? Organizations such as the Predictive Safety Testing Consortium (PSTC) have developed the legal framework needed share the cost of qualification and to protect intellectual property associated with biomarker qualification. Pre-competitive sharing of qualification data is a cost-effective process with which to quickly reach a data threshold for qualification. Does biomarker qualification always require a public process? Qualification requires data generated by companies in industries regulated by specific regulatory agencies. Proprietary qualification data can be shared between companies in regulated industries and their regulatory agencies. These data may or may not be published. Could proposals for biomarker qualification originate from outside the pharmaceutical industry? Yes. The initial proposal for qualification consists of a two-page letter outlining the definition, context and supporting data for the proposed biomarker qualification. Proposals can be received from
Drug Discovery Today: Technologies | Critical path
Industry, Academic, Government or other scientists and clinicians. What are the key steps in the submission of qualification proposals for the Biomarker Qualification Pilot Process? In addition to the initial letter, other steps include: (1) Full submission of qualification data for review by the Biomarker Qualification review Team (BQRT) at the FDA. (2) VXDS meeting to go over the qualification data and to identify potential information gaps before a full review can be completed for the qualification package. (3) Review drafted by BQRT. (4) Internal review at FDA. (5) Communication of decision to sponsor.
Conclusion The need for an accurate, comprehensive and efficient process for biomarker qualification is closely linked with our ability to quickly integrate new biomarkers in drug development and regulatory review. The Biomarker Qualification Pilot Process at the FDA is testing the scientific, clinical and regulatory components for a biomarker qualification process. Experience gained with this currently ongoing pilot process will be useful in the development of a formal regulatory process for biomarker qualification.
References 1 2 3
Goodsaid, F. and Frueh, F. (2006) Process map proposal for the validation of genomic biomarkers. Pharmacogenomics 7, 773–782 Goodsaid, F. and Frueh, F.W. (2007) Implementing the U.S. FDA guidance on pharmacogenomic data submissions. Environ. Mol. Mutagen. 48, 354–358 Goodsaid, F. and Frueh, F. (2007) Biomarker qualification pilot process at the US Food and Drug Administration. AAPS J. 9, E105–E108
www.drugdiscoverytoday.com
11