Schwarz, Adam J, Hill, Derek G, Frisoni, Giovanni, Jack, Clifford, Maguire, Paul and Stephenson, Diane (2013) CAMD/EMA Biomarker Qualification of Hippocampal Volume for Patient Enrichment. Alzheimer’s and dementia.

Abstract

Decreased hippocampal volume (HV) is one of the best established biomarkers to stage the progression of Alzheimer's disease (AD) pathology in the brains of people across the spectrum of the disease [1] (Neurobiology of Aging Dec 2011 special issue). A supporting body of literature over approximately 20 years indicates that changes in hippocampal volume are most rapid around after the onset of dementia. There is substantial evidence that reductions in hippocampal volume, relative to healthy aging, occur at prodromal phases prior to the development of clinical dementia (reviewed by Jack, 2011). It is therefore considered that hippocampal volume represents a biomarker that could be used to enrich clinical trials with individuals who are not yet clinically demented but likely to progress rapidly.
Scientific debate around the use of biomarker(s) in order to enrich a clinical study can be promoted through the recently introduced process of biomarker qualification by global regulatory agencies. . Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that of accelerate appropriate adoption of biomarkers into drug development and, ultimately, clinical practice. Such assurance saves time and money by removing the burden of proof on each individual sponsor to provide data to regulatory agencies on biomarker performance and validation. .
Regulation (EC) No. 726/2004 [2] requires European Community (i.e. central not by single Member State Competent Authority) evaluation of medicinal products for neurodegenerative disorders. In the European Union (EU), the European Medicines Agency (EMA) located in London, UK is the central regulatory agency that reviews new medicinal products. The evaluation is the responsibility of the Committee for Medicinal Products for Human Use (CHMP), which established a Scientific Advice Working Party (SAWP) as one of its supporting Committee to provide scientific advice (SA) to applicants. The SAWP consists of experts in all therapeutic areas and across non-clinical, quality assurance, clinical and biostatistical domains, and includes representatives of the Committee for Orphan Medicinal Products (COMP), the Committee for Advanced Therapies (CAT), and the Paediatric Committee (PDCO). The SAWP thus provides independent expert advice to sponsors seeking marketing authorization. The Qualification of Novel Methodologies procedure [3], established by EMA in 2008, can result in one of two possible outcomes: 1) CHMP qualification advice, or 2) CHMP qualification opinion. Following publication of a draft qualification opinion, the CHMP evaluation is open to scientific scrutiny and public comment to ensure that adopted opinions are broadly accepted within the community. Application to CHMP is entirely voluntary and while sponsors are urged to contact SAWP as early as possible to receive qualification advice, they are allowed to approach the EMA with a dossier in support of a direct qualification opinion.
The Coalition Against Major Diseases (CAMD) is one of five precompetitive consortia of the Critical Path Institute (C-Path) created to deliver on the U.S. Food and Drug Administration’s Critical Path Initiative. The mission of CAMD is to accelerate the development of therapies for Alzheimer’s and Parkinson’s diseases by generating the best methods and tools for evaluating drug efficacy, expediting clinical trials, and streamlining review by regulatory agencies (Romero et al., 2011). CAMD is comprised of members from the pharmaceutical industry, global regulatory agencies, patient advocacy groups, research foundations, government funding agencies, academia, scientific associations, and consultant groups who all work collaboratively in precompetitive, neutral space, aligned in their commitment to combating neurodegenerative diseases. The members of CAMD work to develop tools that can identify patients with neurodegenerative diseases at an early, asymptomatic or mildly symptomatic stage, thereby offering a greater chance for therapies to prevent or slow these diseases so the patients can maintain independence and quality of life for longer and significant periods of time.

In April, 2011, CAMD submitted a dossier to the SAWP requesting a qualification opinion on the use of hippocampal volume as a biomarker for enrichment in AD Trials. SAWP responded with a list of discussion points and questions in May. CAMD submitted a formal written response to several of the questions and then met with SAWP at a face-to-face meeting in June to respond to the remaining questions. At this meeting, SAWP posed several additional questions, and in August, CAMD submitted a formal written response to these questions. In September of 2011, SAWP approved and CHMP adopted the Qualification Opinion on the use of Hippocampal Volume as a Candidate Biomarker for AD [4].
This paper focuses on the content of the data submitted to EMA, the discussion process between CAMD and EMA to address outstanding questions and concerns of the EMA, and the resulting qualification opinion.

Item Type:	Article
Additional Information:	This paper describes the biomarker qualification process for hippocampal volume, including interactions with HAs.
Keywords:	Alzheimers disease, dementia, imaging, hippocampal volume, biomarker, qualification
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9346