![](media/image1.png){width="1.9in" height="1.1in"}March 6, 2000

Dr. Russell Katz, Director, Neuropharmacological Drug Products

Food and Drug Administration FDA 120

1451 Rockville Pike, Room 4049

Rockville, MD 20852-1420

**SUBJECT:** **THE BEHAVIORAL COMMITTEE OF THE INTERNATIONAL WORKING
GROUP FOR THE HARMONIZATION OF DEMENTIA DRUG GUIDELINES STATEMENT TO THE
DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS (DNDP) ISSUE PAPER for
March 9, 2000 Meeting of the Psychopharmacological Drugs Advisory
Committee Meeting on the Various Psychiatric and Behavioral Disturbances
Associated with Dementia.**

Dear Dr. Katz:

We are writing in reference to the hearing the Food and Drug
Administration is holding on March 9 concerning issues related to
developing more effective interventions for the behavioral and
noncognitive symptoms in dementia. We wish to highlight the
international aspects of this issue. This statement has been prepared by
the undersigned of this letter, as Chairpersons of the Behavioral and
Steering Committees of the International Working Group for the
Harmonization of Dementia Drug Guidelines (IWG), and it was approved by
the IWG Steering Committee.

For five years, The International Working Group for the Harmonization of
Dementia Drug Guidelines has been encouraging collaborative efforts
amongst regulators, clinicians, and scientists to define and harmonize
the methods for assessing and treating these symptoms. The FDA draft
guidelines on antidementia drugs have been important in stimulating
global discussions, particularly about cognitive symptoms. We now
believe that the treatment of psychosis in dementia is recognized
internationally as an appropriate target for drug development.

The symptoms in dementia are complex and there can be difficulties in
differentiating cognitive and noncognitive symptoms. Certain symptoms
such as apathy or withdrawal overlap with our traditional two category
conceptual framework for symptoms. The differentiation of visual
illusions and hallucinations can be challenging clinically when they
coexist. Whereas, some behavioral symptoms in dementia can be
categorized into standard psychiatric categories, others cannot.
Moreover, the psychosis of dementia is different from the psychosis
evident in other diseases such as schizophrenia. Depressive symptoms are
frequent, but may overlap in phenomenology with cognitive impairment,
and usually do not reach a level of major depression. Agitation or
restlessness is an important practical problem and yet this symptom is
difficult to fit into standard psychiatric categories. Nevertheless,
operational criteria for psychosis associated with dementia have been
developed and this type of psychosis is an appropriate target for drug
therapy.

We recognize that the principal focus of the upcoming FDA hearing is for
trials conducted in the United States, however, we urge that the
international dimension of this problem be given attention.

p\. 2 - FDA ltr.

In the spirit of the International Conference on Harmonization, the IWG
is working with regulatory bodies around the world to improve the
efficiency of global drug development. We note that the European
Medicines Evaluation Agency (EMEA) Guidelines for dementia trials make
direct references to behavior. However, the EMEA Guidelines do not
specify the designs that might be appropriate for trials in this area.
We expect that the Japanese guidelines may refer to behavioral symptoms
at least in the questions and answers section that will follow the
guidelines. In Canada, the proposed guidelines for the development of
antidementia therapies outline the importance of behavioral symptoms at
a target for symptomatic treatment with the need to demonstrate both
clinically apparent and clinically meaningful treatment effects.

We encourage the FDA to support a consensual multifaceted approach to
developing therapeutic agents in this field. We believe that psychosis
in dementia can be characterized clearly and can be an appropriate and
important target for drug therapy. However, we also believe that
studying and developing treatments for other categories, such as
agitation, is also appropriate.

Thank you for the opportunity to provide comments about this important
topic of psychosis and behavioral symptoms in dementia, a major issue in
the development of drugs to improve the quality of lives in patients
with Alzheimer\'s disease.

Yours sincerely,

***\**Approved but not signed by Jeffrey Cummings**, **Akira Homma,**

and Peter J. Whitehouse

On behalf of the Members of the Steering Committee of the IWG

  ------------------------ -------------------------------- --------------
  Name                     Working Group                    Country

  Serge Gauthier           ADLs                             Canada

  Barry Reisberg           Clinical Global Measures         USA

  Steven Ferris            Cognition                        USA

  Rachelle Doody           Cultural Issues                  USA

  Atwood Gaines            Cultural Issues                  USA

  Zaven Khachaturian       Diagnostic Criteria              USA

  Stephen Post             Ethical Issues                   USA

  Bengt Winblad            Pharmacoeconomics                Sweden

  Leon Thal                Prevention Protocols             USA

  Martin Rossor            Slowing Progression Protocols    UK

  Akira Homma              Behavioral Symptoms              Japan

  Jeffrey Cummings         Behavioral Symptoms              USA

  Jean-Marc Orgogozo       Quality of Life                  France

  Peter Whitehouse         Quality of Life                  USA

  Howard Feldman           Translation Issues               Canada

  Luis Fornazzari          Translation Issues               Canada

  Richard Harvey           Information Technology           UK

  Timo Erkinjuntti         Vascular Dementia                Finland

  Tohru Sawada             Vascular Dementia                Japan

                                                            
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