Critical Path Initiative Opportunities Table
In 2004, the Food and Drug Administration launched the Critical Path Initiative (CPI) to drive innovation in the scientific processes through which medical products are developed, evaluated, and manufactured. In 2006, FDA issued the Critical Path Opportunities Report which provided 6 topics of focus, with a list of 76 opportunities associated with these 6 topics. More information on CPI and the original Critical Path Opportunities report, as well subsequent updates can be found at the FDA website:
Critical Path Institute (C-Path), founded in 2005, is dedicated to developing tools and methods that address these and other opportunities, with the goal of promoting innovation, streamlining drug development and reducing the inherent risks of the drug development and regulatory review process. The work of C-Path and its 12 established consortia, has contributed to many of the opportunities identified by FDA. The tables below summarize the ways in which C-Path has made significant contributions to 19 of the listed opportunities, in five of the six topic areas. The cut-off date for this current table is Dec 31, 2015.
| TOPIC 1 Better Evaluation Tools | |||
| Opportunity # | Opportunity Title | Critical Path Institute (C-Path) Contribution | Status |
| 1 | Biomarker qualification | C-Path helped pioneer the biomarker qualification process and had the first successful biomarker qualification with the FDA, EMA, and PMDA. As C-Path has progressed several sets of biomarkers/tools through the process, it has been involved in working with the FDA and EMA to refine the process. C-Path received several Letters of Support from both FDA and EMA (specific examples noted below). C-Path has also worked to help align the FDA and EMA qualification processes by requesting parallel review. C-Path is currently working with FDA, FNIH BC and other organizations to develop a framework for considering the evidentiary standards required to qualify a biomarker depending on its type and general context of use. C-Path co-sponsored a workshop with FDA and M-CERSI at the University of Maryland on this topic on August 21, 2015. The M-CERSI workshop identified areas that required greater focus as they relate to biomarker development and qualification, and two working groups were formed to begin aligning stakeholders around statistical considerations and important factors to consider in assay validation. C-Path is currently organizing and helping to lead these efforts with team members across multiple biomarker consortia along with scientists from the FDA. | Ongoing |
| 1 | Biomarker qualification |
C-Path’s Arizona Center for Education and Research on Therapeutics (AZCERT) worked together with the American Medical Association on the development of a brochure for prescribers on basic concepts in pharmacogenomics and their application to the specific case of warfarin, highlighting the impact of warfarin dosing algorithms that took into account genetic variances in VKORC1 and CYP2C9. Additionally, the C-Path AZCERT team performed a concordance analysis of the drug-drug-interaction information of the FDA-approved label for warfarin sodium (Coumadin, 2007) and the information contained in three major drug compendia (Clinical Pharmacology, ePocrates, and Micromedex). Of a total of 648 entries from the four sources, only 50 were common to all. This analysis was published: Anthony M, Romero K, Malone DC, Hines LE, Higgins L, Woosley RL. Warfarin interactions with substances listed in drug information compendia and in the FDA-approved label for warfarin sodium. Clin Pharmacol Ther. 2009;86(4):425-9. Subsequently the C-Path AZCERT team performed a concordance analysis of the FDA-approved labels of warfarin and the 50 products common to all compendia (see above). This assessment of official US product labeling for 50 drugs, biologics, and drug classes known to interact with warfarin, comprising 73 distinct agents, found that 15% failed to mention the interaction, even though the interaction was mentioned in the warfarin labeling. This analysis was published in Clinical Therapeutics: Hines LE, Ceron-Cabrera D, Romero K, Anthony M, Woosley RL, Armstrong EP, Malone DC. Evaluation of warfarin drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther. 2011;33(1):36-45. |
Completed |
| 18 | Predicting cardiac toxicity |
C-Path’s Predictive Safety Testing Consortium (PSTC) has a working group focusing on biomarkers to detect drug-induced cardiac hypertrophy. This work is designed to evaluate the response of N-terminal pro-atrial natriuretic peptide (NT-proANP) in rats during maladaptive left ventricular myocardial remodeling induced by pharmaceutical agents. It is hoped that NT-proANP can be used as a screening biomarker in early toxicology studies to detect candidates with the potential to cause cardiac hypertrophy. The working group is currently considering expanding its scope and pursuing the qualification of additional cardiac safety biomarkers. C-Path’s Critical Path to TB Regimens (CPTR) is developing a torsades de pointes (TdP) quantitative platform that will serve as the foundation for supporting recommendations for the rational collection, analysis, interpretation of data, as well as decision-making related to ion channel activity, repolarization reserve information and clinical QT data throughout the development life cycle for novel TB regimens. The first pass of this effort will include collation and review of relevant data pertaining to QT changes with TB drug regimens. CPTR will then develop a quantitative risk-categorization algorithm for drug-induced cardiac arrhythmias (QT prolongation and torsade de pointes), applicable to TB drug development. |
Ongoing |
| 20 | Modernizing predictive toxicology | C-Path’s PSTC has seven working groups looking at new approaches and new predictive biomarkers for detecting and predicting clinical drug-induced toxicity. The mission of PSTC is to identify new and improved translational safety testing methods for use in nonclinical and clinical studies. Many of these approaches are subsequently submitted for formal regulatory qualification. The ultimate goal of the consortium is to improve the current approach to drug safety testing and offer assurance to drug developers that these approaches will be accepted by regulatory authorities for use in drug development programs. The current 18 corporate members of the consortium, including 250 participating scientists, share internal experience with nonclinical and clinical safety biomarkers in seven working groups: Cardiac Hypertrophy, Pancreatic Toxicity, Hepatotoxicity, Nephrotoxicity, Skeletal Myopathy, Testicular Toxicity, and Vascular Injury. All research programs have a strong translational focus in order to select new safety tools that are applicable across the drug development spectrum and advance a comprehensive safety strategy. PSTC is committed to advancing novel approaches to translational safety. | Ongoing |
| 22 | Using medical imaging as a product development tool | C-Path’s Critical Path For Alzheimer’s Disease (CPAD) is working on imaging biomarkers for hippocampal volume as an enrichment biomarker for Alzheimer’s disease (AD), and the use of molecular neuroimaging of the dopamine transporter (DAT) as a prognostic biomarker for enrichment in trials for Parkinson’s disease (PD). CPAD has received letters of support for the use of specific imaging biomarkers for enrichment in clinical trials of AD and PD. FDA has acknowledged and promoted these efforts of CPAD by issuing a Letter of Support for both of these imaging biomarkers in 2015. A link to the letters is below: http://www.fda.gov/drugs/developmentapprovalprocess/ucm434382.htmIn October 2015, C-Path launched a new consortium, Critical Path for Parkinson’s (CPP), which is dedicated to developing tools based on a large aggregated clinical trial database to enable better trial design, including the pursuit of dopamine transport imaging as an enrichment biomarker.The Polycystic Kidney Disease Outcome Consortium (PKDOC) received a Letter of Support from FDA for total kidney volume as an enrichment biomarker in polycystic kidney disease clinical trials on April 23, 2015, followed by DDT qualification on August 17, 2015. EMA qualification was subsequently received on November 6, 2015. |
Ongoing for AD and PD / Completed for PKD |
| 25 | Imaging biomarkers in neurocognitive disease |
As mentioned above, CPAD is working to qualify imaging of hippocampal volume as an enrichment biomarker for Alzheimer’s disease. C-Path is also providing regulatory support to an effort to identify and subsequently qualify biomarkers for use in clinical trials of Traumatic Brain Injury. |
Ongoing |
| 30 | Improving extrapolation from animal data to human experience |
C-Path’s PSTC is looking at the possible translation of their entire portfolio of preclinical toxicity biomarkers into clinical use in humans and their correlation and predictability. In 2014, PSTC received a Letter of Support from FDA encouraging the use of kidney safety biomarkers NGAL and osteopontin to be used in clinical work in order to gain necessary clinical data. A Letter of Support for four circulating biomarkers for skeletal muscle was issued by FDA in 2015. These Letters of Support can be found at: http://www.fda.gov/drugs/developmentapprovalprocess/ucm434382.htm CPTR is undertaking an in vivo pharmacokinetic/pharmacodynamics evidence-based evaluation of animal model predictive accuracy effort: quantifying the translatability of preclinical data to optimize clinical trial design. |
Ongoing |
| TOPIC 2 Streamlining Clinical Trials | |||
| Opportunity # | Opportunity Title | Critical Path Institute (C-Path) Contribution | Status |
| 34 | Design of active control trials | CPTR has several projects that reflect contributions to the design of active control trials. An effort is underway to quantifying the link between the dynamic changes in time to positivity as measured by liquid culture in Phase II studies with clinically relevant endpoints in Phase III trials. In addition, CPTR’s mechanistic systems pharmacology model for TB is quantifying the interaction between bacteria, immune system and drug treatments. CPTR’s Hollow Fiber System for TB (HFS-TB) is qualified by EMA and used to predict clinically relevant findings based on in vitro experiments. Finally, CPTR’s model-based meta-analysis of Phase III quinolone trials is quantifying the relationship between endpoints in these large Phase III trials to evaluate novel anti-TB regimens. | HFS-TB completed / Others ongoing |
| 35 | Enrichment Designs | C-Path is qualifying prognostic biomarkers in Alzheimer’s disease (AD) and Parkinson’s disease (PD) to be used as enrichment strategies in clinical trials. PKDOC has qualified a prognostic biomarker with both FDA and EMA in polycystic kidney diseases (PKD) for use in clinical trial enrichment (see Opportunities #22 and #25). | Ongoing for AD and PD / Completed for PKD |
| 36 | Use of Prior Experience or Accumulated Information in Trial Design |
The Alzheimer Disease Clinical Trial Simulation tool represents efficient use of prior randomized clinical trial (RCT) information to optimize RCT design for mild to moderate Alzheimer’s disease. In 2016, CPAD will undertake an application of this same approach to develop a comparable clinical trial simulation tool for pre-symptomatic and MCI stages of AD. In 2016, CPP will initiate an equivalent effort in PD. CPTR efforts described above in Opportunity #34 are also applicable to this opportunity. |
Completed / Ongoing |
| 38 | Development of trial protocols for specific therapeutic areas |
As part of CPAD’s efforts to qualify imaging biomarkers, CPAD aligns with imaging biomarker experts in the field to develop trial protocols for AD (e.g., Jack et al. Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer’s disease. Alz & Dem.2011;7:474-85). The International Neonatal Consortium (INC) is developing a master protocol for seizures in the neonatal population. |
Ongoing |
| 40 | Measuring disease-related symptoms | C-Path’s Patient-Reported Outcome (PRO) Consortium is working toward qualification of patient-reported outcome measures for the assessment of disease-related symptoms in six therapeutic areas. In addition, symptom-based PRO measures are being considered for development and qualification in multiple sclerosis and myelofibrosis. | Ongoing |
| 41 | Measuring patient-centered endpoints |
C-Path’s PRO Consortium is working to develop and qualify patient-reported endpoint measures for clinical trials in asthma, irritable bowel syndrome, multiple sclerosis, non-small cell lung cancer, rheumatoid arthritis, depression, and functional dyspepsia. The PRO Consortium is also working toward the qualification of a performance outcome tool for assessing instrumental activities of daily living in patients with mild cognitive impairment due to AD. C-Path’s Multiple Sclerosis Outcome Assessments Consortium (MSOAC) is working toward qualifying a performance measure for multiple sclerosis (MS) to assess functional changes associated with MS that significantly impact patients’ daily lives. |
Ongoing |
| 43 | Improving efficacy endpoints in infectious diseases | CPTR’s liquid culture effort is analyzing the predictive accuracy of TB time-to-positivity and two-month culture conversion based on data from three recently completed trials to inform decisions when moving from Phase II to Phase III clinical trials. CPTR efforts described above in Opportunity #34 are also applicable to this opportunity. | HFS-TB completed / Others ongoing |
| 44 | Development of data standards | C-Path has formed a collaborative effort with Clinical Data Interchange Standards Consortium (CDISC), named Coalition for Accelerating Standards and Therapies (CFAST), to develop therapeutic area data standards. Results to date include development and publication of the following 17 CDISC therapeutic area standard user guides (all v1.0 unless otherwise noted): Alzheimer’s v1.0 and v2.0, Asthma, Cardiovascular, Chronic Hepatitis C, Diabetes, Dyslipidemia, Influenza, Multiple Sclerosis, Pain, Parkinson’s Disease, Polycystic Kidney Disease, QT Studies, Schizophrenia, Tuberculosis, and Virology v1.0 and v2.0. In process (all v1.0 unless otherwise noted) are: Traumatic Brain Injury, Breast Cancer, COPD, ADaM Supplement to Diabetes, Diabetic Kidney Disease, Tuberculosis v2.0, Rheumatoid Arthritis, CV Imaging, Prostate Cancer, Major Depressive Disorder, General Anxiety Disorder, Bipolar Disorder, and Kidney Transplant. Seven additional projects are planned: Oncology Colorectal, Oncology Lung, Psoriasis, Duchenne Muscular Dystrophy, Clostridium difficile Associated Diarrhea (CDAD), Post-Menopausal Osteoporosis, and Skin and Skin Structure Infections. |
Completed / Ongoing |
| TOPIC 3 Harnessing Bioinformatics | |||
| Opportunity # | Opportunity Title | Critical Path Institute (C-Path) Contribution | Status |
| 46 | Identification and qualification of safety biomarkers | C-Path’s PSTC has qualified seven preclinical kidney safety biomarkers with the FDA, EMA, and PMDA. They have received Letters of Support for additional kidney safety biomarkers and skeletal-muscle safety biomarkers. PSTC is also working on safety biomarkers for liver injury, cardiac hypertrophy, vascular injury, pancreatic injury, and testicular toxicity. | Ongoing |
| 51 | Clinical trial simulation |
C-Path’s CPAD has developed and received endorsement from FDA and EMA for a clinical trial simulation tool for mild to moderate Alzheimer’s disease (AD). This represents the first-ever such regulatory endorsement for quantitative drug development platforms. Preliminary planning has been done for a clinical simulation tool to be developed for Parkinson’s disease (PD) by the CPP consortium, and for Duchenne muscular dystrophy (MD) by the newly formed Duchenne Regulatory Sciences Consortium (D-RSC). D-RSC was launched in 2015 with an initial goal to develop a disease progression model for Duchenne MD. CPTR efforts described above in Opportunity #34 are also applicable to this opportunity. |
Completed for Alzheimer clinical trial simulation and HFS-TB / Ongoing for other projects |
| 53 | Natural history database for rare diseases |
The PKD database, compiled by PKDOC and available online, is a database containing longitudinal data describing the natural history for Autosomal Dominant Polycystic Kidney disease, which has been granted orphan status to the pharmaceutical company Otsuka. The D-RSC is currently building a natural history database for Duchenne MD. |
Completed for PKDOC / Ongoing for D-RSC |
| TOPIC 5 Developing Products to Address Urgent Public Health Needs | |||
| Opportunity # | Opportunity Title | Critical Path Institute (C-Path) Contribution | Status |
| 67 | Improving antimicrobial product testing | C-Path’s CPTR initiative is evaluating and sponsoring validation of several drug development tools for TB, including a hollow fiber in vitro testing system to measure efficacy of new combination therapies for TB (this tool was qualified by EMA on January 22, 2015), and quantifying liquid culture as prognostic indication of relapse. CPTR is launching a data platform, called ReSeqTB, to inform the development of new rapid drug sensitivity tests for TB to enable the implementation of new drugs and drug regimens. CPTR is also working on several models, from a physiologically based pharmacodynamic model to a population-based disease progression model. | HFS-TB completed / Others ongoing |
| TOPIC 6 Specific At-Risk Populations: Pediatrics | |||
| Opportunity # | Opportunity Title | Critical Path Institute (C-Path) Contribution | Status |
| 72 | Better extrapolation methods and best practices in pediatric trial design |
C-Path has formed a new consortium to address the needs and challenges of developing drugs for a neonatal population. The International Neonatal Consortium (INC), launched May 2015, will engage the global neonatal community (families, healthcare providers, academics, advocacy organizations, and pharmaceutical companies) to focus on the development of safe and effective therapies for neonates. INC is developing a master protocol for seizures in the neonatal population, and developing models that can be used to extrapolate test results into neonatal populations is high on the list of potential outcomes. The Pediatric Trials Consortium (PTC), launched in October 2015, will create a new nonprofit organization to organize a pediatric clinical trials network to focus exclusively on regulatory quality clinical trials with innovative medical products in order to more efficiently facilitate the development of drugs, biologics, and devices for children. |
Ongoing |
| 73 | Drug metabolism and therapeutic response [pediatric population] | INC will focus specifically on neonatology and the challenges of drug development in this arena. A white paper is underway on considerations regarding safety, dosing, and pharmaceutical quality for studies that evaluate medical products in neonates. | Ongoing |