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Core Competencies and Key Concentration Areas of the Critical Path Institute

C-Path is an independent entity that provides the legal, scientific, and regulatory infrastructure to generate a unique neutral environment for relevant stakeholders in the medical product development ecosystem to collaborate. This collaboration allows the sharing of information and data, which serves as the foundation for C-Path to spearhead the transformation of such information and data into actionable solutions that address specific unmet needs in the medical product development process. Such solutions can include data resources, biomarkers, clinical outcome assessment tools, clinical trial simulators and other quantitative tools. These tools and solutions help de-risk decision making in the development and regulatory review process of novel medical products. This makes C-Path a unique source of expertise working to achieve many of the objectives outlined in the U.S. Food and Drug Administration’s (FDA) report “Innovation / Stagnation — Challenge and Opportunity on the Critical Path to New Medical Products.”

 

1DATA MANAGEMENT AND STANDARDS

C-Path’s core competency in data management and standards development enables the effective integration of multiple diverse data sources into actionable databases that allow the generation of solutions to expedite medical product development and facilitate the regulatory review process. C-Path has a close and long-standing relationship with the Clinical Data Interchange Standards Consortium (CDISC). CDISC is a recognized standards-setting organization whose standards are required for new NDA and IND submissions to the FDA. C-Path worked with CDISC to develop the first therapeutic area data standards and has led the efforts in many more, including Alzheimer’s disease, Parkinson’s disease, polycystic kidney disease, tuberculosis, multiple sclerosis, Duchenne muscular dystrophy and others. Approved data standards are published for use by the scientific research community on CDISC’s website . More recently, C-Path has begun working with Observational Health Data Science and Informatics (OHDSI) to contribute to the clinical trials and registries working groups of the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). We are also contributing to and reusing ontologies from the Open Biological and Biomedical (OBO) Foundry.

C-Path’s Data Collaboration Center (DCC) was instituted to provide large-scale data resources as the foundation for the generation of actionable solutions to optimize the medical product development process. The DCC team has more than a decade of experience in data standards development, ontology development, platform development, platform hosting, data curation, stewardship of patient-level data privacy, data security and access control methodologies. DCC’s work takes place in a neutral, non-competitive environment and utilizes appropriate data standards. C-Path has developed and continues to maintain databases for all indication-focused consortia at C-Path, of which those for Alzheimer’s disease, Parkinson’s disease, tuberculosis, multiple sclerosis, Duchenne muscular dystrophy, Friedreich’s ataxia and polycystic kidney disease are also accessible to qualified researchers here . DCC’s unique abilities have been instrumental in the generation of a modern, cloud-based data and analytics platform which is being utilized in the Rare Disease Cures Accelerator and Alzheimer’s disease efforts. Additional information about three types of databases C-Path has generated can be found here , they include:

  • Integrated patient-level databases for multiple diseases
  • Genetic sequencing of pathogens
  • Collection of nonclinical and clinical biomarker data

 

2BIOMARKERS

Transforming translational sciences is another key component of the modernization of the medical product development process. C-Path leads the way in regulatory qualification of biomarkers and was the first organization to qualify biomarkers with the FDA, European Medicines Agency (EMA) and Japan’s Pharmaceutical and Medical Devices Agency (PMDA). The following C-Path consortia have successfully qualified biomarkers with regulatory agencies:

  • Predictive Safety Testing Consortium (PSTC): FDA, EMA and PMDA qualified six nonclinical urinary biomarkers for the detection of acute druginduced nephrotoxicity in rodents.
  • Critical Path for Alzheimer’s Disease: EMA qualified the baseline measurement of low hippocampal volume (atrophy) by MRI to predict whether such patients are likely to evolve to Alzheimer’s diseasetype dementia during the course of an Alzheimer’s disease clinical trial. In 2015, the FDA provided a Letter of Support (LOS) for cerebrospinal fluid analytes and hippocampal volume as exploratory prognostic biomarkers for enrichment in earlystage AD trials, and more recently, EMA gave the first-ever LOS for the pre-dementia disease progression model and clinical trial simulator that incorporates hippocampal volume.
  • Polycystic Kidney Disease (PKD) Outcomes Consortium: FDA and EMA qualified Total Kidney Volume as a prognostic biomarker for enrichment of clinical trials in autosomal dominant PKD based on a quantitative disease and biomarker progression model. Subsequently, through direct interactions with the Division of Cardiology and Nephrology, TKV was designated as a reasonably likely surrogate endpoint for PKD trials.

 

3MODELING AND ANALYTICS

Model-Informed Drug Development (MIDD) has become a main area of investment to modernize the medical drug development process. MIDD is based on the discipline of modeling and simulation, which has been a key area of expertise for C-Path since its inception. The vision of C-Path’s Quantitative Medicine (QuantMed) Program is to transform drug development through methodological innovation and MIDD. QuantMed also works to drive innovation in MIDD through partnerships with leading groups and organizations in the field, and through collaborations with societies such as the International Society of Pharmacometrics, the American Society for Clinical Pharmacology and Therapeutics, and the American College of Clinical Pharmacology.

The development of these tools is possible thanks to the standardized integration of clinical and data analytical knowledge to solve bottlenecks in the drug development process. C-Path collaborated with scientists in industry to develop the first endorsed quantitative drug development platform:

  • The clinical trial simulation tool for mild-to-moderate Alzheimer’s disease (first-ever quantitative drug development tool to be endorsed by FDA and qualified by EMA).
  • The pre-dementia disease progression model (also known as the “Conrado model”), which incorporates HV as an enrichment biomarker (firstever quantitative drug development tool to receive a Letter of Support from EMA).
  • Development of several quantitative drug development tools for tuberculosis, including the EMA-qualified hollow-fiber system for this disease (HFS-TB).
  • Development of the model-based qualification of total kidney volume as an enrichment biomarker of trials in polycystic kidney disease, which also provided the supporting evidence for its declaration as a reasonably likely surrogate.
  • The quantitative clinical trial enrichment tool for early-motor Parkinson’s disease utilizing dopamine transporter imaging as an enrichment biomarker, qualified by EMA.

Currently, QuantMed is developing clinical trial simulation tools for Parkinson’s disease, Duchenne muscular dystrophy, Alzheimer’s disease, type 1 diabetes and Huntington’s disease. Additionally, model-based biomarker qualification efforts are underway for trial optimization in type 1 diabetes prevention studies and kidney transplant trials.

 

4REGULATORY/ DEVELOPMENT SCIENCE

The core competencies described above are facilitated by C-Path’s strengths in integrating all efforts for the benefit of advancing regulatory science through multiple avenues. This includes not only the support for formal submissions for regulatory review and potential endorsement of solutions to accelerate medical product development, but also the development of consensus among experts and stakeholders within and across C-Path efforts. Such consensus is exemplified through white papers, peerreviewed publications and other documents that help disseminate the institute’s efforts, as well as inform the generation of optimized scientific paradigms for an efficient medical product development process. C-Path has provided public feedback on numerous draft guidance documents released for comment by both FDA and EMA.

C-Path has been instrumental in leading the movement within the scientific community to more clearly articulate the level of evidence necessary to achieve the regulatory endorsement of specific drug development tools through the appropriate regulatory mechanism at specific regulatory agencies. This is one of the most challenging issues in the drug development tool qualification process.

In April 2016, key stakeholders including FDA’s Center for Drug Evaluation and Research, C-Path and the Foundation for the National Institutes of Health Biomarkers Consortium held a workshop to develop an evidentiary criteria framework for safety biomarker qualification. The resulting white paper delineated the proposed framework and provided specific examples of its applicability to clinical safety biomarkers. In May of 2021, a collaborative group of authors from the pharmaceutical industry, the CRO sector, NIH, FDA, academia and C-Path published a peer-reviewed article pertaining to perspectives on statistical strategies related to the process of regulatory qualification of biomarkers.

* Note that despite the equivalent terms, LOS is a formal mechanism with EMA

 

5CLINICAL OUTCOME ASSESSMENTS

Patient-centric drug development is a key aspect of optimal medical product development. By working with numerous stakeholders around the globe, C-Path has emerged a leader in the development and regulatory endorsement of patient-reported outcome measures and other clinical outcome assessments (COAs). C-Path’s Patient-Reported Outcome (PRO) Consortium provides a collaborative framework for the development and qualification of COAs that can be used to optimize the evaluation of efficacy of novel medical products. In addition to efforts aimed at advancing electronic collection of COA data on existing and emerging data capture technologies more broadly, C-Path’s Electronic Patient-Reported Outcome (ePRO) Consortium works closely with the PRO Consortium to make the COAs advanced by its therapeutic area working groups available in various modes of data collection. While multiple COAs are in development or other stages of qualification, the following PRO measures have obtained formal FDA qualification and are being actively deployed in clinical trials today:

  • Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD)
  • Diary for Irritable Bowel Syndrome SymptomsConstipation (DIBSS-C)
  • Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ)
  • Symptoms of Major Depressive Disorder Scale (SMDDS)
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