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The Predictive Safety Testing Consortium and the Coalition Against Major DiseasesDiane Stephenson and John-Michael Sauer

The Predictive Safety Testing Consortium and the Coalition Against Major Diseases, both launched by the Critical Path Institute, provide valuable examples of the outcomes and lessons learned by different types of consortia working on new drug development tools.

The Critical Path Institute (C-Path) has launched seven consortia to date. Although all consortia support regu-latory decision-making through the development of tools designed to evaluate the efficacy or safety of drugs, some consortia focus on specific diseases (for example, the Coalition Against Major Diseases (CAMD) for Alzheimer’s disease and Parkinson’s disease) and others target cross-cutting needs of drug developers (for exam-ple, the Predictive Safety Testing Consortium (PSTC)). This article highlights key outcomes and lessons learned as these two different types of consortia worked with regulatory agencies to obtain endorsement of new drug development tools (DDTs).

The Predictive Safety Testing ConsortiumThe tests used to define the safety of a drug candidate have not substantively changed in decades. Although companies have developed newer safety testing methods, these approaches have only been used internally because they are not generally accepted by regulatory agencies as contributory proof of safety. In part, this is because the approaches often differ from company to company, which leads to uncertainty about which methods are pre-ferred by regulatory agencies. In addition, the methods have not been independently validated.

Through the PSTC, members are able to share their expertise, resources, data and internally developed approaches in a neutral, precompetitive, confidential envi-ronment. There are more than 250 participating scientists, with C-Path serving as the ‘trusted third party’ leading the collaborative process by collecting and summarizing the data, facilitating interactions with health authori-ties and driving the projects through milestones based on consensus science. Moreover, the PSTC has sought synergistic interactions with other consortia that have similar scientific objectives. For example, the PSTC has been collaborating for several years with the Biomarkers Consortium on the Kidney Safety Project with the goal of

qualifying clinical translational kidney safety biomarkers. More recently, collaboration has begun between the PSTC and the Innovative Medicines Initiative (IMI) Safer and Faster Evidence-based Translation (SAFE-T) consortium to qualify clinical translational kidney, liver and vascular safety biomarkers.

To date, the PSTC has qualified seven biomarkers of nephrotoxicity for use in preclinical toxicology studies in order to allow exploratory usage in early development clinical studies. The US Food and Drug Administration (FDA; in 2008), the European Medicines Agency (EMA; in 2008) and the Japanese Pharmaceuticals and Medical Devices Agency (in 2010) have issued formal regulatory opinions that these biomarkers can be utilized on a volun-tary basis in good laboratory practice (GLP) rat toxicology studies to monitor drug-induced kidney injury1,2.

The PSTC continues to work towards additional bio-marker qualifications for use in both nonclinical and clini-cal drug development. The ultimate goal of the PSTC is to improve the current approach to drug safety testing and offer assurance to the drug developers that the improved approaches will be acceptable to regulators. With the objective of qualifying quantitative safety biomarkers, the PSTC is positioned to lay the foundation for toxicomet-rics — defined as the science that quantifies drug, toxicity, and trial information to aid efficient drug development, regulatory decisions and rational drug therapy.

The Coalition Against Major DiseasesRecent failures of therapeutic candidates for Alzheimer’s disease and Parkinson’s disease highlight the need for inno-vative approaches, as well as the value of public–private partnerships (PPPs). The CAMD creates new technolo-gies and methods to accelerate the development of medical products for neurodegenerative diseases through a part-nership of pharmaceutical companies, patient advocacy organizations, key academic experts, and governmental research and regulatory agencies. Formal qualification of

Diane Stephenson is Executive Director of the CAMD, and John-Michael Sauer is Executive Director of the PSTC, at the Critical Path Institute, 1730 East River Road Tucson, Arizona 85718, USA. e-mails: DStephenson@c-path.org; JSauer@c-path.orgdoi:10.1038/nrd4440

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DDTs and novel methodologies by regulatory agencies has widespread implications, in that there is broad applica-bility across multiple drug candidates independently of the mechanism of action of the drug or of the sponsor.

The CAMD is active in several areas including data sharing, quantitative disease modelling, improved out-come measures and biomarkers. The consortium shares patient-level data from legacy clinical trials, develops new tools to be submitted to regulatory agencies and creates consensus data standards. Since its 2008 launch, significant milestones have been achieved. The first is the develop-ment of consensus data standards: in partnership with the Clinical Data Interchange Standards Consortium (CDISC), the CAMD co-developed therapeutic area data standards for Alzheimer’s disease (v1.0 in 2010 and v2.0 in 2013) and, along with the US National Institute of Neurological Disorders and Stroke (NINDS), CDISC standards for Parkinson’s disease (in 2012). The second is the develop-ment of a unified clinical trial database: CAMD members contributed individual patient-level data from placebo arms of clinical trials to develop a pooled database on which the development of novel tools and methods depends; addi-tionally, the CAMD made this pooled data set available to qualified researchers3. The third is qualification by the EMA of low baseline hippocampal volume (assessed by MRI) as an enrichment biomarker for clinical trials in pre-dementia stages of Alzheimer’s disease3. Fourth, a clinical trial simulation tool designed to aid in trial design for mild and moderate Alzheimer’s disease was recently endorsed by both the FDA and the EMA, representing the first example of a regulator-endorsed drug–disease–trial model4 (see Further information). Now available through the C-Path website, the Alzheimer’s quantitative disease model repre-sents a milestone that should encourage the advancement of drug–disease–trial models for a variety of diseases.

Overcoming the challengesBoth the CAMD and the PSTC have broken new ground in establishing cross-sector communities and delivering tools and methods that support decision-making in drug development. Although much has been achieved, future success is challenged by several issues in several areas that need to be addressed.

The first is defining and expanding the precompeti-tive space. Given the revenues associated with successful drug development, concerns may arise about enabling the competition. To date, this has not been a major impedi-ment for collaboration in the PSTC, as improvements in approaches to drug safety must be aligned across all of industry and the regulators. However, greater incentives for industry to share information and avoid duplication of effort are a critical future need. Here, patient groups could have an impact by advocating for greater collaboration.

The second is greater data sharing; perceived risks as well as lack of consent for secondary use of patient data are just two of the numerous barriers. Again, patient groups and patients could help in catalysing a path forward.

The third is navigating ‘consortia fatigue’. The suc-cess of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Parkinson’s Progression Markers Initiative (PPMI) have demonstrated the transformative

benefits of precompetitive models, but the growing number of partnerships can also be counterproductive if accompanied by duplication of efforts, fragmentation of approaches and/or dilution of resources. The need to align across PPPs has been recognized by the PSTC and the CAMD. However, initiating cross-consortia collabora-tions is made difficult in many cases by the legal construct that defines individual consortia.

The fourth is funding. The current funding climate means diminished in-kind and monetary resources for executing on consortia deliverables. Disease foundations have played a key role in funding multiple disease-focused consortia, and it is important for these contributions to continue if there is to be more success in the future. However, disease foundations do not generally support cross-cutting consortia such as the PSTC. Now that the PSTC and the CAMD can draw on past experience to estimate the time and cost of qualifying a DDT, potential funders can prioritize and support individual projects.

The fifth is communicating value. The novelty of DDT qualification brings an increased need for defining and communicating the pharmacoeconomic impact and the return on investment (in terms of time, reduced risk or cost savings) for developing these tools in order to justify continued support for future collaborative efforts.

ProspectusThe true value of the work done by consortia such as the CAMD and the PSTC is that every company does not need to reproduce or validate previously published data to support individual drug development efforts. Instead, the process of regulatory endorsement of a DDT allows for the expedited use of novel approaches with less regula-tory risk and greater scientific certainty. The evolving sci-entific landscape poses both challenges and opportunities for drug developers. Only by working in concert can all the relevant data be shared, analysed, transformed into an accepted and widely adopted DDT, and modified as addi-tional data accumulate to produce the best tools possible.1. Sistare, F. D. et al. Towards consensus practices to qualify safety

biomarkers for use in early drug development. Nature Biotech. 28, 446–454 (2010).

2. Dieterle, F. et al. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nature Biotech. 28, 455–462 (2010).

3. Hill, D. et al. CAMD/EMA biomarker qualification of hippocampal volume for enrichment of clinical trials in pre-dementia stages of Alzheimer’s disease. Alzheimer’s Demen. 10, 421–429 (2014).

4. Ito, K. et al. Understanding placebo responses in Alzheimer’s disease clinical trials from the literature meta-data and CAMD database. J. Alzheimers Dis. 37, 173–183 (2013).

AcknowledgementsD.S and J.-M.S. would like to thank L. Hudson for her contributions to this article. Funding for PSTC and CAMD included Science Foundation Arizona grant number SRG 0335–08 and US FDA grant number U01FD003865.

Competing interests statementThe authors declare no competing interests.

FURTHER INFORMATIONCoalition Against Major Diseases: http://c-path.org/programs/camd/Disease Specific Model Library: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm180485.htmPredictive Safety Testing Consortium: http://c-path.org/programs/pstc/Qualification opinion of a novel data driven model of disease progression and trial evaluation in mild and moderate Alzheimer’s disease: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2013/10/WC500151309.pdf

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