Alzheimer’s Consortium Regulatory Successes, Letters of Support and Timeline
C-Path’s Critical Path for Alzheimer’s Disease (CPAD) has accrued a number of successes and achievements since its inception in 2008. View the consortium’s regulatory successes and letters of support, and history of impactful achievements below.
Letters of Support
The US Food and Drug Administration (FDA) issued a Letter of Support for cerebral spinal fluid (CSF) analytes Aβ1-42, total-tau, and phosphor-tau as exploratory prognostic biomarkers for enrichment in AD trials.
US FDA Letter of Support (February 26, 2015)
This letter, issued to CAMD, describes the FDA’s thoughts on early intervention in AD, and the importance of identifying patients with mild cognitive impairment (MCI) who are likely to develop further cognitive impairment within the time frame of a clinical trial, to potentially lead to therapies with greater impact. The FDA encourages the inclusion of these exploratory CSF biomarkers in clinical trials to evaluate their utility in clinical trial enrichment.
The US Food and Drug Administration (FDA) issued a Letter of Support for low baseline hippocampal volume (HV) measured by magnetic resonance imaging (MRI) as exploratory prognostic biomarkers for enrichment in AD trials.
US FDA Letter of Support (March 10, 2015)
This letter, issued to CAMD, describes the FDA’s thoughts on the value of measuring hippocampal atrophy over the course of a clinical trial. The FDA encourages the exploration of the possible use of low baseline HV (as measured by MRI) for the purpose of clinical trial enrichment.
/The CPAD team has developed a non-linear mixed effects model for the longitudinal trajectory of Clinical Dementia Rating – Sum of Boxes (CDR-SB), based on patient-level data from the ADNI-1 and ADNI-2 trials. The Investigation Into Delay to Diagnosis of Alzheimer’s Disease With Exelon (InDDEx) trial was used as an external validation dataset. The model accounts for baseline intra-cranial volume-corrected hippocampal volume (ICV-HV), apolipoprotein E4 (APOE-ɛ4) carrier status, baseline MMSE scores, baseline age and CDR-SB, as well as sex as other relevant covariates. This model allows the user to perform simulations to inform sample size estimation and power calculations, as well as evaluating enrichment strategies, over a varied range of assumptions and trial design options.
Current approaches for sample size estimation, based on literature metadata of the estimated standard deviation for the clinical endpoint and the expected effect size, do not account for differences in clinical and demographic characteristics of the enrolled trial population, disease worsening profile over time, and the different levels of variability (e.g., between-study, between-subject, and residual variability). The current version of the model accounts for the contribution of the aforementioned aspects and is being used to develop a web-based aMCI clinical trial simulator with a user-friendly graphical interface. This tool will simulate clinical trials based on user-defined trial and subject characteristics at study entry.
The EMA supports the primary objectives of the applicant and has decided to issue a Letter of Support to the CPAD Consortium to encourage industry sponsors to share the patient-level data from completed phase II and III clinical trials in the intended target population as defined in the COU statement, including active and control arms, with CPAD. This will allow the CPAD team to complete the development and validation of the proposed quantitative novel methodology in drug development, while also encouraging the CPAD team to disseminate and provide access to the current version of the model for implementation by sponsors actively designing clinical trials in
FDA and EMA Qualifications
The goal of the proposed simulation tool is to serve as a public resource for sponsors designing trials of new therapies for Alzheimer’s disease (AD). CAMD intends that this simulation tool will provide quantitative support in the design and planning of clinical trials involving subjects with mild to moderate AD. The submission further suggests that the proposed tool could be used during all clinical stages of AD drug development, including proof-of-concept, dose-ranging, and confirmatory trial design and could encompass various types of treatment mechanisms (e.g. symptomatic and disease-modifying). The submission outlines several intended applications of the proposed tool:
- Sample size calculations
- Determination of optimal trial durations and treatment effect measurement times • Comparison of the sensitivity of competing trial designs to assumptions about the types of expected treatment effects (time to maximal effect, effects that increase or decrease over time)
- Determination of the most appropriate data analytic methods for novel trial designs
On 20 March 2013 the Applicant Critical Path Global Ltd. requested qualification opinion for the proposed Disease Progression and Trial Evaluation Model.
The context of use: “The proposed Disease Progression and Trial Evaluation Model, as defined in this document, is suitable for qualification for use in Drug development as a longitudinal model for describing changes in cognition in patients with mild and moderate AD, and for use in trial designs in mild and moderate AD.”
Dr. David Brown was appointed as coordinator. The Qualification Team comprised of: Dr. Susan Morgan Mr. Rob Hemmings, Dr. Ferran Torres, Dr. Bertil Jonsson, Dr. Monique Wakelkamp, Dr. Valentina Mantua, Prof. Luca Pani. The Patient representative for the procedure was Mr. Jean Georges. The EMA Scientific Administrator for the procedure was Dr Maria Isaac.
The procedure started during the SAWP meeting held on 02 – 04 April 2013.
The Qualification Team meeting took place on 07 May 2013. The discussion meeting with the Applicant took place on 04 June 2013. During its meeting held on 03 – 06 June 2013, the SAWP agreed on the opinion to be given to the Applicant.
During its meeting held on 24 – 27 June 2013, the CHMP adopted the opinion to be given to the Applicant. Excluding commercially confidential information, the draft qualification opinion was released for public consultation on the 19 July 2013 to 27 August 2013.
During its meeting held on 2-4 September 2013, the SAWP agreed on the final opinion to be given to the Company. During its meeting held on16-19 September, the CHMP adopted the final opinion to be given to the Company.
The opinion given by CHMP is based on the claims and supporting documentation submitted by the Company, considered in the current state-of-the-art in the relevant scientific fields.
The European Medicines Agency’s (EMA) qualification process is a new, voluntary, scientific pathway leading to either a CHMP opinion or a Scientific Advice of novel methodologies on innovative methods or drug development tools. It includes qualification of biomarkers developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry for a specific intended use in pharmaceutical research and development.
The Qualification team was: Prof. Fernando de Andrés Trelles (coordinator), Prof. Luca Pani (CHMP member), Dr Bertil Jonsson, Christine Gispen de Wied. The EMA Scientific Administrator for the procedure was Dr Maria Isaac.
On 23 March 2011 the Applicant C-Path CAMD Biomarker Working Group requested qualification advice for the Candidate Biomarkers of Alzheimer’s Disease (AD).
The procedure started during the SAWP meeting held on 26 – 28 April 2011. The discussion meeting with the Applicant took place on 29 June 2011.
During its meeting held on 30 August – 01 September 2011, the SAWP agreed on the advice to be given to the Applicant. During its meeting held on 19 – 22 September 2011, the CHMP adopted the advice to be given to the Applicant.
The response given by CHMP is based on the questions and supporting documentation submitted by the Applicant, considered in the light of the current state-of-the-art in the relevant scientific fields.
Timeline
Launched CPAD-led tau PET Surrogacy Working Group.
Published two manuscripts on tau PET harmonization under review at Alzheimer’s & Dementia
Eclipsed 97,000 patient-level data in AD repository.
Initiated development bi-directional quantitative modeling platform.
Launched CPAD-led tau PET Harmonization Working Group.
Initiated collaboration with Global Alzheimer’s Association Interactive Network (GAAIN) for a harmonized image analysis pipeline.
Eclipsed the 36,000 mark in patient-level data in CPAD Repository.
Initiated modeling plan.
Eclipsed 20,000 patient-level data in AD repository.
EMA Letter of Support: Mild Cognitive Impairment Simulation tool.
CAMD renamed to Critical Path for Alzheimer’s Disease (CPAD).
FDA Letter of Support: Trial enrichment tool for amnestic Mild Cognitive Impairment.
Connect AD Database with Global Alzheimer’s Association Interactive Network (GAAIN).
FDA Letter of Support: Low Hippocampal volume as exploratory prognostic biomarker for AD clinical trials.
FDA Letter of Support: CSF (11-442), t-tau, and p-tau as exploratory biomarkers for trial enrichment
EMA Qualification: Drug development tool for trial simulation in Mild to Moderate AD Dementia.
FDA Fit-for-Purpose Qualification: Trial simulation tool in Mild to Moderate AD Dementia.
First AD Clinical data Interchange Standards Consortium (CDISC) standards published.
First integrated patient-level database for AD was created.
Coalition Against Major Diseases (CAMD) was launched to enhance regulatory decision-making tools to advance drug development and improve the lives of those living with Alzheimer’s disease and related dementia (ADRD). Later renamed to Critical Path for Alzheimer’s Disease (CPAD).
