Tuesday, 22 June 2010

By streamlining the qualification process for biomarkers, coordinated protocols recently implemented at the different regulatory agencies can facilitate progress and provide impetus to novel biomarker discovery and validation.

Since the sequencing of the human genome was first announced in 2000, regulatory agencies in the United States (The Food and Drug Administration; FDA, Rockville, MD), Europe (European Medicines Agency, EMEA; London) and Japan (the Pharmaceuticals and Medical Devices Agency, PMDA; Tokyo) anticipated the potential impact of this new knowledge on drug development and together initiated a series of fact-finding international conferences with the objective of obtaining input from the pharmaceutical industry and other stakeholders. Several initiatives have since been developed to address the need for sharing knowledge and risk associated with the use of the new genomic methodologies in drug research and development.

In 2003, under the framework of the bilateral confidentiality agreements between the European Union (EU; Brussels) and the FDA1, FDA and EMEA scientists held joint discussions with sponsors on Voluntary Genomic Data Submission (VGDS) packages. The success of the initial experience with these meetings led in 2004 to an expanded VGDS process2, including the option for sponsors to have joint FDA-EMEA VGDS briefing meetings. A joint document3 explains how such requests are received, processed and reviewed by the agencies. In 2005, regulatory agencies in the United States4, the EU5 and Japan6 issued guidelines or requests for the submission of genomic information from the R&D pipelines. These documents served several purposes: they encouraged voluntary submission of genomic data by sponsors to these agencies; they described how the agencies process VGDS data (that is, submissions that are not required as part of a regulatory submission) and the associated discussion meetings; and they emphasized that voluntary submissions are used to help the agencies gain an understanding of genomic data and are not part of the regulatory decision-making processes.

Over recent years, VGDS meetings and other interactions with sponsors at the FDA, EMEA and PMDA have suggested extensive progress in the development of exploratory biomarkers. The FDA and EMEA consider that many research activities have been under way within the pharmaceutical and biotech industry to qualify biomarkers, but that many of the data generated by these activities remain within the firewalls of individual companies. These data are shared neither among companies nor with regulatory agencies.

In this article, we describe the efforts of the various regulatory agencies to establish a mechanism to facilitate the sharing of biomarker data. By encouraging the establishment of public-private partnerships and consortia, these efforts have served as a catalyst for noncompetitive pooling of data with the objective of achieving a critical mass of data, enhanced knowledge about biomarkers and a consensus on how biomarkers should be applied both at the preclinical stage and ultimately in the clinic.
Setting the stage

Several strategic documents, such as the FDA's Critical Path Initiative7, the EMEA's “Road Map to 2015” (ref. 8), and the recent report from the European Medicines Agency Innovation Think-Tank group9, have focused on the importance of support by regulators in this area, with the ultimate objective of ensuring that new technologies are taken up in pharmaceutical R&D to promote the development of safe and efficacious new medicines for the benefit of patients. Several consortia, such the Critical Path Predictive Safety Testing Consortium10 and the EU Innovative Medicines Initiative11, are today generating substantial data that may overlap or complement each other and also influence regulatory standards, which require proper regulatory appraisal to encourage their application in R&D. Regulatory agencies not only have been deeply involved in supporting biomarker integration in pharmaceutical R&D through scientific advice starting from the early stages of product development but also aim to provide a scientifically robust and predictable set of requirements for the evaluation of data in Marketing Authorization Applications (MAAs), Investigational New Drugs Applications (INDs), New Drug Applications (NDAs) or Biologic License Applications (BLAs).
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At the international level, the joint activities of the EMEA Pharmacogenomics Working Party and the FDA Interdisciplinary Pharmacogenomics Review Group have established a working model for global regulatory review of exploratory biomarker data. On this basis, and in view of the advances in the field, the regulatory agencies have developed dedicated processes to deal with biomarker qualification. These biomarker qualification processes address the need of individual organizations and consortia asking for a regulatory qualification of the results obtained from the ongoing collaborative efforts. Such a path has been tested in these biomarker qualifications. This process is focused on the specific needs of the regulatory environment to ensure scientifically accurate and clinically (or preclinically) useful decision-making.
The biomarker qualification process

The Predictive Safety Testing Consortium (PSTC) application for the qualification of seven new renal biomarkers as predictors of drug-mediated nephrotoxicity is the first experience of this new joint-agency review process put in place by US and European drug regulators. At this time, the qualification of these biomarkers covers voluntary submission of these data for rat studies. On a case-by-case basis, the FDA and the EMEA will also consider other possible applications of these biomarkers in early clinical trials. The tests measure levels of seven key proteins or biomarkers that scientists from the FDA and EMEA believe provide important new safety information about the effect of drugs on the kidney. When reviewing INDs, NDAs or BLAs, both regulatory agencies can now consider the test results in addition to blood urea nitrogen (BUN) and serum creatinine (SCr) data12.

The long-term implementation of this process will reflect knowledge and experience gained as additional biomarker qualification submissions are received and reviewed. The process itself is likely to succeed if qualification data are selected and submitted to accurately support a specific context of use. The most difficult part of this process will be to define incremental contexts of use and the corresponding evidence with which biomarkers may be qualified.

The desired goals in regard to public health in this case would be to obtain better biomarkers of nephrotoxicity for routine clinical use as quickly as the data will allow, but intermediate qualification contexts and data need to be defined so that investment in biomarker qualification studies will be productive both for clinical use as well as for the pharmaceutical and biotech industry.

Initial studies proposed by consortia are unlikely to match a clear context for qualification for a full clinical application of biomarkers. What intermediate contexts for qualification can we define? What study characteristics can we propose for qualification in these intermediate contexts of use? Several authors (e.g., see refs. 13,14) have proposed evidentiary recommendations for biomarker qualification. In contrast to this incremental process for biomarker qualification, papers on evidentiary recommendations often propose all-or-nothing qualification contexts, where if the ultimate goal is a clinical qualification, no intermediate qualification contexts are expected to be defined or qualified. This approach is not only time-consuming but also unlikely to encourage the investment needed to generate data for biomarker qualification. At each stage, whether the context of use for a biomarker is to be in vitro, in a nonclinical animal model or in the clinic, a company or consortium proposing the qualification of a biomarker will likely seek a quick return on that qualification once data are available to qualify the biomarker in a specific context in drug development. An effective process for biomarker qualification should include incremental application context steps, so that these incremental steps can fit into and benefit the drug development process.
Steps in submission for biomarker qualification

The first step in drafting a submission for qualification of a biomarker is to determine its context of use, in advance of specific decisions on applicable structure and format. The context of use for a biomarker is (i) the general area of biomarker application, (ii) the specific applications and implementations and (iii) the critical factors that define where a biomarker is to be used and how the information from measurement of this biomarker is to be integrated into drug development and regulatory review. To demonstrate the alignment between proposed context and data, the initial context proposal must be supported by data available at the initial application step or expected to be available throughout the data evaluation process. There is a convergent relationship between an initial qualification context and the data supporting it.

The initial gap between proposed context and data may need to be filled throughout the qualification process. Initial context proposals, however, should project a significant improvement over currently available biomarkers and/or endpoints. The context of a biomarker drives data requirements to demonstrate its qualification for the intended application. The structure of a submission document ensures that the context and data can be submitted in a package that is consistent for consortia submitting qualification as well as for reviewers in regulatory agencies evaluating a qualification package. The structure of a qualification submission is independent of the context of this submission but must also be flexible enough to deal with the specific requirements of each context. The format of data required to qualify a biomarker may vary significantly with the context in which it is to be used and with specificities of each biomarker considered.

In addition to joint efforts by individual regulatory agencies, an effort to harmonize the submissions for qualification of genomic biomarkers has been initiated through the International Conference on Harmonization (ICH) framework. The ICH E16 Working Group has developed a draft guideline15 summarizing how the context of use for the biomarker may be defined and how the structure of the submission and data formats are to be integrated. The harmonization of documents such as this is likely to have an impact well beyond the document itself. The harmonization for the submission document is a precedent that should help address the fear that often permeates the discussion of biomarker qualification. This precedent will also facilitate future harmonization efforts for other aspects of qualification.
Past, present and future of biomarker qualification

Biomarker qualification is not a new concept. Biomarkers have been accepted through several ad hoc pathways in each regulatory agency. At both the FDA and the EMEA, biomarkers have been qualified in recent years on a case-by-case basis, in which the application context of use for the biomarker is always drug dependent. Biomarker qualification is also implicitly integrated in regulatory review of drug-test co-development16. Finally, a sui generis qualification is also implicit when biomarker information is added to a preexisting drug label. This experience is reflected in the “Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels”17 on the FDA website. In this case, the context of use for the biomarker is explicitly linked to text in the labels for one or more drugs.

The VXDS at the FDA, the Joint FDA-EMEA VXDS briefing meetings with sponsors, and the dedicated qualification procedures implemented at the FDA and the EMEA18 open opportunities for the qualification of biomarkers not only directly connected to an individual product development but also with a wider relevance in the assessment of drug efficacy and safety. These processes will need to be tested in the near future with submissions for qualification of biomarkers from a diverse range of platforms, nonclinical and clinical areas, biotech and pharmaceutical companies, diagnostic companies and academic institutions. The evolution of this process and its usefulness for drug development will accelerate as new examples of novel biomarkers are brought through for qualification.

Source: Nature Biotechnology