Tuesday, 22 June 2010

A medicine is defined as 'a substance or preparation used in treating disease'. Society expects that the benefits of medicines should substantially exceed their risks, and this expectation has been translated into governmental policy around the world. Part of the mission of the US Food and Drug Administration (FDA) is to protect the public health by assuring the safety and efficacy of medicines¹. The FDA has carried out its mission by relying upon the best current scientific knowledge and practice². By definition, gaps in current scientific knowledge and practice limit the ability of regulatory agencies, such as the FDA and the European Medicines Agency (EMEA; London), to carry out their mission. Current gaps include a limited ability to extrapolate animal data to humans^{3, 4, 5}, the difficulty of evaluating genetic and carcinogenic risks^{6, 7}, and our poor understanding of gender-specific responses⁸. It is hoped that new knowledge, technologies and tools can address these and other gaps and improve the evaluation of new drugs and medicines^{9, 10, 11, 12}.

In this context, the FDA has advocated a 'Critical Path Initiative'^{13, 14} to intentionally address gaps in applied and regulatory science. The initial report and subsequent listing of specific opportunities¹⁵ called attention to research and tools needed to improve the process of drug development that extends from preclinical testing to ultimate regulatory registration. Although this area is vital for improving the development of new medicines and getting them to the public, it receives little academic, public or legislative attention and, thus, little funding. Rather, the focus of both academic research and news organizations is often on novel discoveries and/or the risks and benefits of drugs after they have reached the marketing phase. Nevertheless, a great deal of essential work must be accomplished between discovery and delivery (that is, in the critical path) to accomplish the delivery of safe and effective medicines to the public. With the goal of improving that process, the FDA has not only identified gaps in 'Critical Path Research' but also suggested that an effective approach to address these gaps would be to form consortia of industry, academic and regulatory scientists to share resources, expertise and experience toward accomplishing shared common specific objectives.

Consortia have played key roles in addressing technological problems common to a competitive industry. For instance, the Sematech consortium, formed in 1987 and comprising 14 leading US semiconductor producers, addressed common issues in semiconductor manufacture and increased R&D efficiency by avoiding duplicative research¹⁶. Sematech demonstrates that consortia provide the opportunity for industry scientists to share their experiences in identifying and solving problems, to pool their expertise and to collectively consider mutual questions. To create similar models in drug, diagnostic and device development, the Critical Path Institute (C-Path) was incorporated as a “neutral, third party” to serve as a consortium organizer¹⁴ and interface between industry members and the FDA¹⁷.

One of the first consortia formed by C-Path to address one of the Critical Path gaps was the Predictive Safety Testing Consortium (PSTC)^{18, 19}. As noted in the Critical Path Opportunities list, there is a need for “preclinical biomarkers that predict human liver or kidney toxicity” and “collaborations among sponsors to share what is known about existing safety assays”¹⁵. Indeed, the preamble to the legal agreement that binds PSTC members notes that “the parties to this Agreement also recognize the importance of validated safety biomarkers to pharmaceutical and biotechnology research and development efforts and wish...to conduct research and development projects, under the coordination of C-Path, to identify and validate such biomarkers to increase drug safety.” Thus, the PSTC is committed to cooperative research resulting in tools beneficial to both pharmaceutical development and regulatory science (termed Critical Path Research). Of course, these tools could be valuable to medical situations where improved monitoring for drug safety would improve outcomes.

The PSTC legal agreement furnishes not only a clear set of goals and deliverables that provide guidance for actions and decisions of the consortium, but also a framework to address issues such as antitrust, intellectual property and confidentiality. This assures open data sharing and collaboration in a manner consistent with applicable legal requirements. In particular, the confidentiality provisions also assure that publications (which are encouraged) respect member contributions, again fostering openness and participation. As noted above, C-Path provides executive functions and contributes overall scientific leadership, whereas members lead strategic and technical execution of the scientific working groups pursuing biomarkers of several critical toxicities where understanding of new biomarkers is desired. Members also participate in an advisory committee that, among other functions, reviews new proposals and ongoing projects and guides their scope and growth.

A key component of Critical Path Research is the participation and critical evaluations of the very regulatory scientists who will later rely on the results obtained with these new tools as they are applied to the development of new pharmaceuticals. Participation of FDA scientists in PSTC is made possible by a memorandum of understanding between C-Path and the FDA. In addition, the PSTC has representatives from the EMEA who, like FDA scientists, serve to advise the target-organ biomarker working groups (e.g., the Nephrotoxicity Working Group and the Hepatotoxicity Working Group); as experts in their respective fields, these advisors bring not only their expertise but also the experience of how problems of a given target-organ toxicity will need to be confronted in a regulatory setting. The biomarker data generated by a working group is ultimately reviewed by a different set of regulators, thus safeguarding an impartial scientific evaluation and recommendations for how the biomarkers may be used in regulatory decision making.

Implicit in the formation and the goals of the PSTC is the realization that the current approach to the discovery, development, industry uptake and regulatory acceptance of new safety biomarkers is simply too slow and too inefficient to meet the growing needs of the worldwide healthcare system. For example, serum alanine aminotransferase was described as a marker for liver damage in the early 1960s and now is widely used for that purpose²⁰. Even so, it has never been rigorously evaluated as a nonclinical or clinical marker for hepatocellular damage (e.g., by receiver operator characteristic curves analysis²¹), its specificity for detecting such damage remains in question, and defined cut-off values for patient monitoring in clinical trials are only now gaining consensus agreement^{22, 23}. Newly discovered biomarkers suffer from a similar liability in not having a clear or expedient path for reaching a consensus as to their value and specific terms of use.

Thus, one goal of the PSTC is to establish an intentional process for developing data sets that would support the use of a given biomarker for a specific purpose. This process, appropriately termed biomarker 'qualification'²⁴, should be distinguished from technical validation of a biomarker assay²⁵. Wagner²⁶ describes this qualification process as the “fit-for-purpose evidentiary process of linking a biomarker with biological processes and clinical endpoints,” and notes that a certain body of data may support one purpose, whereas a larger body of data may support a broader purpose²⁶. Clearly, this process must entail interaction between those developing the data set and regulatory scientists, and a framework for beginning that dialog has now been created²⁷. Importantly, the result of such an exchange would be a clear statement or guidance from regulatory authorities as to the acceptable uses of a given biomarker in support of medical product development and registration. Furthermore, the process should allow the expansion of those qualified uses after the development of a larger, relevant body of biomarker data, aptly described as “progressive qualification.”

The papers in this issue describe critical recent accomplishments of the PSTC for the regulatory qualification of kidney safety biomarkers for preclinical applications. In particular, urinary biomarkers were considered, as this fluid passes unmodified through the ureter and bladder to the exterior, is easy to archive and its contents offers a monitor of kidney function. The standard biomarkers for kidney injury, serum creatinine (SCr) and blood urea nitrogen (BUN) are widely recognized as highly insensitive, and thus measures with improved sensitivity are desired²⁸. Several PSTC companies had internal experience with other biomarkers for kidney toxicity, and, after sharing these data, determined that seven biomarkers in particular showed promise for higher sensitivity than SCr and BUN and had technically sound assays available for their measurement. Furthermore, histopathology in animal models of nephrotoxicity was tractable as a metric against which the urine biomarker performance could be compared.

An open collaboration among 17 pharmaceutical/biotech companies, regulatory bodies and academia has generated a data set supporting the qualification of several new biomarkers of drug-induced kidney injury. In addition, this effort, with the involvement of the FDA and EMEA, explored pilot processes for optimization of content, structure of presentation and expectations for regulatory review of similar data sets. The collaboration extends beyond that between scientists in competing companies, academic scientists and regulatory scientists, to that between regulatory scientists in different jurisdictions. The power of these collaborations has as its proof the speed at which the data set was developed, the process of review put into place and the establishment of an initial model that future biomarker qualification efforts can follow. PSTC is also a testimony to the benefits that can be derived from productive open collaborations between academia, regulatory agencies and the private sector. For an area of research long neglected, these accomplishments are all the more noteworthy.

Source: Nature Biotechnology