isctm « ISCTM | The International Society for CNS Clinical Trials and Methodology

WASHINGTON–(BUSINESS WIRE)–Continuing in their mission to promote advances in the development and use of CNS therapeutic agents, the International Society for CNS Clinical Trials and Methodology (ISCTM) met February 21, 2011 in Washington, D.C. to discuss one of the most important issues facing the field today. (Full Release)

The International Society for CNS Clinical Trials and Methodology (ISCTM) commends the FDA for preparing a draft of the comprehensive Guidance for Industry, “Qualification Process for Drug Development Tools”.

The ISCTM is a multi-disciplinary independent organization, devoted to promoting advances that address strategic clinical, regulatory, methodological and policy challenges that arise in the development and use of CNS therapeutic agents. This work is accomplished through partnership with persons in academia, industry, government, policy-making and the public. Recognizing the importance of this document for our constituency, the ISCTM convened a
working group of its members to review and comment on the guidance.

Workgroup members included:
Chairs: Douglas Feltner, MD, Douglas E Feltner, LLC
Michael Davidson, MD, Sheba Medical Center, Israel
Judith Abdalla MD, Quintiles, Inc.
Munaf Ali MD, Munaf Ali Consulting
Larry Alphs MD, PhD, Ortho-McNeill Janssen
Stacey Boyer, Pfizer, Inc.
Marc Cantillon MD, Critical Path Institute (C-Path)
Michael Detke MD, PhD , MedAvante
Richard Keefe PhD, Duke University Medical Center
Herbert Meltzer MD, Vanderbilt University
James Mundt PhD, Center for Psychological Consultation
Tanya Ramey MD, PhD, Pfizer, Inc.
Dennis Revicki PhD, United BioSource Corporation
Henry Riordan PhD, Worldwide Clinical Trials, Inc.
Gary Sachs MD, United BioSource Corporation
Stephen Sainati MD, PhD, Takeda Pharmaceuticals International, Inc.
Cate Stasio, Brain Plasticity Institute
Monica Vance, Santium Group Inc.

General Comments: The ISCTM believes that having a defined process for DDT developers to interact with the FDA to qualify new drug development tools will facilitate bringing new drugs to market. Comments on specific aspects of the draft guidance are below.

1) Line 18: Currently, many PROs and rating scales, and a few biomarkers are used in drug development and are generally accepted by virtue of their use as being qualified for the purposes they are used for. It would be helpful for the guidance to say clearly that it is intended to describe a process for qualifying new drug development tools (those that do not already have regulatory acceptance for a certain use). The guidance should indicate that drug development tools that have a current use with prior regulatory acceptance are considered to be qualified.

     2) The ISCTM supports the use of one guidance for describing the qualification process for all classes of DDTs. The document was not clear, given the varying classes of drug development tools (DDTs) that could be covered by the guidance, where language used in the guidance applies to all classes of DDTs and where the language applies only to a specific DDT class. (Line 119, for example, refers only to PROs, and not other types of rating scales, and this should be indicated. In lines 179, and 191, for example, references to a single qualification for use in multiple clinical disorders would not apply to many PROs or rating scales, since these are typical qualified for an intended population.) Specific issues related to this general issue are raised below.
          a. Line 19, Line 112: The guidance needs to be more specific on the types of tools that are covered. In addition to new PROs and new biomarkers, the ISCTM believes that new clinician-administered rating scales, new rating scales administered through automated methods (interactive voice response, other computerized methods and devices), remote (e.g. teleconference and videoconference) clinician assessments, new diagnostic rating questionnaires, new safety questionnaires, and new tools for cognitive assessment should be covered by the guidance.
          b. Line 99, Section IIIB, Appendix 3 and Appendix 5: The distinctions between qualifying PROs, clinician-administered rating scales, and automated methods of rating scale administration are not well-made and would benefit from clarification. Alternatively, an additional section paralleling the content of section IIIB (PROs), and additions made to Appendices 3 and 5, could be added to more specifically discuss clinician administered rating scales, and automated methods of administration of rating scales and questionnaires.
          c. Lines 126, 144, 164, 200, 325: It would be helpful for the reader if the document were organized in such a way that a reader interested in a particular class of DDT can find that information without having to sort through information on other classes of DDTs that are not of interest. This can be done by adding information to the heading of each section to indicate whether it applies to all DDTs or only a particular subclass (where this has not already been done).

     3) Several issues related to the Qualification Review Team (QRT) and the qualification decision-making process should be clarified:
          a. Line 261-264: The functional roles (clinician, statistician, technology expert, biomarker expert, PRO expert, etc) that will generally be expected to compose the FDA, QRT should be identified. The leadership of the QRT should be clarified. The composition of the QRT may differ, depending on the type of DDT being developed. . It would be helpful to have the proposed composition of the QRT communicated to the DDT development consortium and to allow the DDT development consortium to suggest functional roles that it believes should be included on particular DDT.
          b. Lines 266 and 359: It would be helpful for the guidance to specifically identify a primary point of contact at the FDA to deal with communications with external tool developers. The primary point of contact could differ, depending on the DDT class and the stage of tool development.
          c. Line 261, Lines 320-322: The administrative entity (office, division, etc) that constitutes the QRT and that provides the final decision on whether qualification has occurred should be indicated in the guidance. If this differs for different classes of DDTs, that should be indicated.

4) Lines 320-322: The guidance should indicate whether FDA decisions on qualification of DDTs can be appealed by the DDT developer prior to issuance of the particular draft qualification guidance, the time-frame, and how to do so.

5) Line 200, Section V: It would be helpful for the guidance to provide standard or anticipated amounts of time for the FDA to respond to and provide advice on the DDT Letter of Intent; to respond to the briefing package and hold the briefing package meeting; to provide subsequent advice during stage 1; to review, respond to, and complete the Stage 2 review for a qualification decision following submission of the formal qualification package.

6) Section V, VI: It would be helpful to add an overall flow diagram showing the various stages of the process in a pictorial format.

     7) The guidance is envisioned to provide a degree of generalizability of use of a tool “across multiple clinical disorders, multiple drugs, or drug classes.” (p 5, ll 178-180) The guidance also specifies that the qualification of a DDT is limited to a clearly defined “context of use” (p 4, ll 134-135). Prior FDA guidance on the use of PROs to support labeling claims indicates PROs must be validated separately in each patient population, a position reinforced by the definition provided for “Context of Use.” (p 18, ll 657-658) It is suggested that the qualified context of use may be modified, expanded, or even withdrawn as additional data are collected submitted and analyzed (p 6, ll 233-236), the process and procedures for accomplishing such are unclear.
          a. Lines 134-135, 178-180,657-658, and biomarkers sections and biomarker appendices: The ISCTM believes that the generalizability of a DDT may depend in part on the class of DDT. Safety biomarkers, for example, might be more readily generalizable across populations than PROs and clinician rating instruments. Clarifying comments in the document on DDT generalizability across disorders and populations with respect to which class of DDT is being referred to is needed.
          b. Lines 233-234: The guidance should clarify whether review and re-qualification processes for expanding the applicability of a DDT that has been qualified though this process will be assigned to the same QRT that conducted the initial review, or whether a different QRT would or might be constituted. Will all qualification expansions need to re-start at the beginning of the process and complete the entire process, or might certain steps of the process might be skipped when adding new uses to a drug development tool previously qualified by this process?
          c. Line 235-236: The guidance should clarify the process for DDT qualification withdrawal. The withdrawal of a qualified DTT could have a substantial impact on ongoing drug development programs or on approved labeling and as such there should be an opportunity in the process for public involvement and an indication of how the FDA will work with impacted sponsors.

8) Lines 200-207: The ISCTM believes that coordinating this qualification process with other major ex-US regulatory agencies could be useful, so that separate, sequential qualification processes are not required for each major region or country. The guidance could indicate whether this is considered a possibility . In general, regulatory experience that is public would be extremely helpful to reference. The renal biomarkers that have completed qualification and the ongoing PRO processes handled by Critical Path Institute, as well as the ongoing DDT in Coalition Against Major Diseases (CAMD), are useful examples.

9) Lines 227-231; Line 315: The process should include the opportunity for full public comment prior to the final qualification decision. While many drug development tool consortia may have very broad expertise and be very inclusive, others may not. The engagement of an expert panel or advisory committee-like body may also be useful.

10) Section V and VI: Can the FDA address whether a fee will be charged for initiating the process and whether paying the fee would result in guaranteed FDA response times for each of the stages of the qualification process, along the lines of the IND/NDA process?

12) Line 95: change “quantitative predictions” to “quantifiable predictions”

ISCTM Working Group Dinners Report

Six Working Group Dinners were held at the recent ISCTM 7th Annual Scientific Meeting in Washington DC. These dinners were highly interactive and met with great enthusiasm from the participants. The ISCTM extends sincere thanks to the chairs of these groups: Adaptive Design – Ginger Haynes; Suicidal Assessment – Adam Butler, Michelle Stewart; Placebo – Amir Kalali, Larry Ereshefsky; Mitochondrial Systems – Charles Bowden; Negative Symptoms – Stephen Marder, David Daniel and Biomarkers – Larry Alphs, Karl Broich.

Summaries of the work conducted at these groups will be posted on the Working Group webpage, where you will also find other details regarding ISCTM Working Groups. If you are interested in joining a working group, please contact the Secretariat. Working groups are open to ISCTM members only.

Developing Products for Personalized Medicine: Facing the Challenges of Biomarkers

As our field moves toward an increasingly personalized approach to medical treatment, biomarkers (including genomic, proteomic, imaging, etc.) become increasingly important for informing clinicians about the relative safety, tolerability, efficacy and outcomes values for CNS products. In addition, biomarkers can serve to help screen for new therapeutic agents, identify susceptible populations, provide endpoints for trials and, potentially, predict efficacy, safety and outcomes of clinical trials. This increasing interest raises challenges for many different stakeholders regarding the structure and elements of clinical trials that are needed to establish scientific data around biomarkers. This session will bring clinicians, designers of clinical trials, regulators, statisticians and payers together to more clearly identify issues relative to the use of biomarkers to meet these needs. It will include formal presentations from experts, and will provide examples of how biomarkers have been used in the Alzheimer’s field as an exemplar of hurdles to this work and how they might be addressed. In the afternoon, workshops led by experts will give practical experience in how to incorporate biomarkers in clinical trials and establish their value. The results of these workshops will be reviewed by senior experts in the field.

2011 Mental Health Research-to-Policy Forum

Impact of National Health Reform and Shifting National Priorities on Mental Health Research-to-Policy-to-Implementation

· Where are the alignments and the differences between the data policy makers need, the data researchers are providing, and the data needed to improve public mental health?

· What are meaningful endpoints to consumers, advocates, payers and policy makers?

Do Clinical Developments to Date Suggest that Drug Development Based on the Amyloid Hypothesis is Dead?

Substantial pre-clinical evidence support an amyloid hypothesis as a key causative factor in Alzheimer’s Disease (AD). Genetic studies (knock out animals, population assessments in patients) suggest a link between beta-amyloid deposition in the brain and reduced cognitive capacity. Additionally, the findings from ADNI appear to support a strong association between ‘amyloid’ burden as measured by PET, and significant shifts in CSF A Beta to tau protein ratios with disease progression (prodrome-MCI-Mild/Moderate). Concurrent to ADNI, pharmaceutical companies are developing amyloid-based treatments aimed at slowing or preventing the progression of AD. Recently, the results of several treatment studies targeting amyloid have been reported, demonstrating disappointing results. This session brings together academic, pharmaceutical , and regulatory perspectives to:

Class Labeling: Implications for Treatment and Challenges to Differentiation in Development

Over the last decade, a number of safety issues regarding medicines used to treat neurological and psychiatric conditions have led to class labeling for events such as suicidality (antidepressants, AEDs), metabolic disturbances (atypical antipsychotics) and CV/stroke (atypical antipsychotics in elderly patients with dementia). This has created challenges for clinicians who must make important choices about individual treatment, often without the necessary skills to assess risk at the patient level. Given that the communication of risk in labeling is evolving, the utility of the information currently provided may not necessarily meet the needs of the prescriber. This session will review the evidentiary standards that contribute to the determination of a class label. Specific questions to be addressed include what, in fact, makes a “class” a “class” (shared mechanism? shared targeted indication?); what determines that a product group will have such labeling; and what are the implications for practice, in particular, physician decision-making regarding choosing the right medicine for an individual patient. Current standards for safety capture in phase 2/3 development programs, as well as conventions for safety data display and descriptions in labeling, will be reviewed. Regulatory agency representatives from the United States and the European Union will present regulatory views, addressing evidence requirements and any concerns regarding implications for prescribers and patients. Agency representatives will additionally be asked to highlight any potential future approaches to the display or communication of safety information that could lead to enhanced utility to the prescriber. Emphasis will be placed, during facilitated discussions, on how individual product data might be provided for a specific safety parameter, even in light of that medicine having a class label for that particular safety parameter (for instance, if evidence for class labeling came from pooled/meta-analyses, could a single product’s data be provided in label even in light of “lack of individual signal”). Implications for drug development will be discussed.

Session Summary: Mitochondrial Systems as Targets for Development of Novel Pharmacological Interventions in CNS Disorders Are Addressed at ISCTM 2010 Autumn Conference

A half-day session, characterizing the role of mitochondria dysfunction in various CNS disorders and the utility of targeting specific aspects of this dysfunction was chaired by Charles Bowden, MD, Professor and former Chairman of the Department of Psychiatry at University of Texas Health Science Center and Andrew Nierenberg, Professor of Psychiatry and Director, BipolarResearch Program at Massachusetts General Hospital, Harvard Medical school, was held on October 14, 2010, at the 210 Autumn Conference Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Baltimore, Maryland.

The session began with a review of basic physiology of the electron transport chain and the role of mitochondria which has been implicated in the formation and maintenance of various neurodegenerative and psychiatric disorders based on numerous lines of evidence including abnormal calcium metabolism, brain energy metabolism, reactive oxygen species and mitochondrial associated genetic defects. Dr. Nierenberg noted that “although some disorders arise directly from mitochondrial DNA mutation, some stem from nuclear gene mutation, and for many disorders the etiology remains elusive. It is important to note that while there are only 37 mitochondrial genes, there are over 1,200 genes that code for proteins in mitochondria making the task of targeting gene systems very daunting.”

With a focus on near term applicability Dr. Bowden utilized Depression and Bipolar Disorders as examples of possible methodologies that could be employed in targeting mitochondrial systems citing the utility of certain medication such as valproate, lithium, and gabapentin in bipolar disorder and their effect on calcium signaling, synaptic functioning, histone deacetylase inhibition, apoptosis, neurogenesis and possibly even neuroprotection. These compound along with several lines of data from animal models and molecular evidence have confirmed the role of mitochondria in bipolar disorder. Dr. Bowden also noted that many well known neurodegenerative diseases including ALS, Huntington’s, Alzheimer’s and Parkinson’s disease which have long been known to be a result of mmitochondria that are physically or functionally altered are also associated with behavioral and psychiatric symptoms. Dr. Bowden called for “the need to work more closely with the our neurologist colleagues in order to discover new targets based on underlying pathophysiology as we simply cannot venture into this novel arena with the same strategies that we have used in the past”.

Evidence was also provided for possible utility of already existing drugs and drug combinations that potentially modify mitochondrial systems such as acetyl- L–carnitine plus alpha lipoic acid, N- acetyl-cysteine (a glutathione precursor), Coenzyme Q10 as well as several methodological paradigms to assess their potential efficacy such as measuring brain activity at rest (aka default mode brain), magnetic resonance spectroscopy (especially the N acetyl aspartate to chorine ratio), and structural and functional MRI (fMRI). Additionally, DNA microarray technology to analyze gene-expression profiles in the postmortem brain and novel animal models to assess mitochondrial system deregulation are needed to improve targetability of drugs aimed at correcting mitochondria dysfunction.

This session reviewed the many challenges faced when identifying and testing potential mitochondria targets including the complexity of the electron transport chain system dysfunction which can both drive and mediate disease, the lack of known central biomarkers, poor brain penetrance of possible drugs, and the time period that is likely needed in order to change a dynamic system – with some evidence that typical studies of chronic psychiatric disorders which usually assess drug effects between 8 and 12 week duration would not be sufficient long to see changes.

At the conclusion of the session it was unanimously agreed that the session chairs and attendees should form the foundations of a Mitochondria Targets Working Group moving forward with future collaboration and reporting of efforts in the form of future ISCTM sessions and a white paper. Presentations and video of the session are currently being posted for viewing by ISCTM Members, accessible through the ISCTM Library.

The ISCTM (isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The 6th Annual Scientific meeting will be held February 21-23, 2010 at the Fairmont Hotel, Washington DC. View Preliminary Agenda (Submitted by H. Riordan).

Author Archive

Concerns Regarding Amyloid Hypothesis in Alzheimer’s Disease Addressed at 7th Annual Meeting

AWARDS AND FUNDING OPPORTUNITIES

ISCTM Conflict of Interest

Acceptance and Disclosure Statement

ISCTM Comment FDA DDT