**MEMORANDUM**

**DATE: February 6, 2001**

**TO: Members, Peripheral and Central Nervous Systems Drugs Advisory
Committee and Invited Guests**

**FROM: Staff**

**Division of Neuropharmacological Drug Products**

**SUBJECT: Background Document for PCNS Meeting of March 13, 2001:
Issues Related to the Development of Treatment for Mild Cognitive
Impairment**

# Background

As you know, a meeting of the Peripheral and Central Nervous System
Drugs Advisory Committee of the Food and Drug Administration will be
held on March 13, 2001 to discuss the entity of Mild Cognitive
Impairment. This paper has been prepared in an effort to brief you on
the specific issues that we believe need to be addressed by the Agency
when considering the regulation of drugs being developed to treat this
putative clinical entity. In addition to this memo, we are forwarding a
number of articles from the literature addressing several important
aspects of this issue, which we hope will provide a more detailed
background for the meeting.

## Purpose Of Meeting

The purpose of this Advisory Committee meeting is to achieve a consensus
on a number of issues related to the proposed entity of Mild Cognitive
Impairment (MCI). These issues, which are discussed further below, are
being raised in the context of the development of drugs intended for the
treatment of that putative disorder.

## Mild Cognitive Impairment

MCI is a widely referred-to concept in publications that deal with
age-related cognitive disorders and dementia.

Several operational definitions of MCI have been proposed in the medical
literature, and in drug trial protocols that our Division has reviewed.
One such definition refers to a population that has isolated memory
impairment, no other areas of cognitive abnormality, and normal or only
slightly impaired functional abilities. Other definitions use criteria
that are based on scores achieved on cognitive and global rating
instruments, and are not necessarily restricted to isolated memory
impairment.

Populations considered to have MCI based on these definitions have, in
prospective studies, been reported to have a variable, but increased
risk of developing overt Alzheimer\'s Disease over time, as compared
with age-matched controls. Such reports appear to be the main reason why
MCI has been considered a target for pharmacological intervention.

Clinical drug trials for the proposed entity of MCI have had 2 main
objectives when assessing the efficacy of a putative treatment. These
consist of evaluating the benefit of the drug in:

-   preventing or delaying the onset of Alzheimer's Disease in this
    population

-   treating the cognitive abnormality of MCI

There can be no question that the goal of preventing or delaying the
onset of Alzheimer's Disease, or of any other form of dementia, in a
susceptible population, is a commendable and highly desirable one.
However, from a regulatory perspective, a number of issues need to be
addressed in regard to the development of drugs to treat this putative
entity.

Currently both the concept and proposed definitions for MCI appear to be
controversial, based on a reading of the medical literature.

## FDA Role

The FDA approves a drug for marketing based on a determination that such
a treatment is both effective and safe, when used to treat one or more
specific clinical entities. The entity for which such a treatment is
intended, is referred to as the "claim" or "indication" for that drug
and is described in the "Indications and Usage" section of the label.
Proposed labeling must accompany the New Drug Application (NDA)
submitted by the sponsor.

The Federal Food, Drug, and Cosmetic Act (the Act) requires that the
approval of a drug treatment for a specific condition be supported by
(among other things) "...substantial evidence that the drug will have
the effect it purports or is represented to have under the conditions of
use prescribed, recommended, or suggested in the proposed labeling...".
Substantial evidence is further defined as evidence from "adequate and
well controlled...clinical investigations...". These definitions make
clear that approval of a drug product is inextricably linked to our
ability to adequately describe the population for whom the drug is
intended and the drug's effects in that population in labeling.

In order to do this, the following must generally be true:

-   The condition can be defined without ambiguity using criteria that
    have wide acceptance, and are both valid and reliable

-   Appropriate instruments be used for measurement of the clinical
    effect of the drug on that condition; such instruments must measure
    what they are intended to under the conditions under which they are
    actively employed

-   Clinical trials should be appropriately designed to measure that
    effect

-   The effect measured should be clinically meaningful

For the most part, 2 classes of clinical entities are considered
appropriate for new drug claims

-   Specific diseases or clinical syndromes, such as multiple sclerosis
    or chronic renal failure.

-   Non-specific symptoms such as pain or urinary frequency

On occasion, claims may be also be directed at symptoms of specific
diseases, e.g., excessive daytime sleepiness associated with narcolepsy.

The Act also states that the Secretary may refuse to approve an
application "if based on a fair evaluation of all material facts, such
labeling is false or misleading." Labeling that states that a particular
drug is indicated for the treatment of a specific clinical entity could
be considered misleading if the condition if not well-defined, the
effect of the drug on that condition is not appropriately measured, or
the clinical trial in which that effect was measured was not
appropriately designed.

In deciding whether a proposed clinical entity justifies a new claim,
criteria used by the FDA have generally consisted of the following

-   The existence of the entity must be broadly accepted by medical
    experts representing the relevant clinical discipline

-   The entity should be operationally definable

If a new claim is sought for a drug that is already approved for a
specific indication, a sponsor would be required to establish that the
new indication is meaningfully different from the existing claim.
Otherwise, the implication in labeling that the 2 indications were
different entities when, in fact, they were not, could be considered
misleading.

## Current Basis For Approving Drugs For Dementia

In the last 10 years 3 drugs have been approved by the FDA for the
treatment of dementia: tacrine, donepezil and rivastigmine. All 3 drugs
have been approved for an identical indication: the treatment of mild to
moderate Alzheimer's Disease. Their approval has been based upon
clinical trials, the key elements of which have been as follows

### Diagnosis of Alzheimer's Disease 

Patients enrolled in these trials have generally had "probable"
Alzheimer's Disease as defined by the National Institute of Neurological
and Communicative Disorders and Stroke and the Alzheimer's Disease and
Related Disorders Association (NINCDS-ADRDA). Those criteria\* are as
follows

-   Dementia established by clinical examination, and confirmed by a
    rating scale such as the Mini-Mental Status Examination, and by
    neuropsychological testing

-   Deficits in two or more areas of cognition

-   Progressive cognitive worsening

-   No disturbance of consciousness

-   Onset between ages 40 and 90

-   Absence of systemic disorders, and other brain diseases that could
    account for the progressive cognitive impairment

\*The NINCDS-ADRDA criteria for probable Alzheimer's Disease have been
shown to be both valid and moderately reliable. They have a sensitivity
of \> 90%; their specificity is however lower (50 -- 60%) and they are
particularly lacking in specificity in distinguishing the frontotemporal
dementias from Alzheimer's Disease, as well as in distinguishing those
who have a combination of cerebrovascular neuropathology and Alzheimer's
Disease from those who have pure Alzheimer's Disease.

### Severity Of Dementia

Patients enrolled in these trials have been considered to have dementia
of mild to moderate severity at study entry. The severity of their
dementia has been assessed based on their Mini-Mental Status Examination
scores; the range of such scores that have been considered to fit the
"mild to moderate" category has been from 10-26.

### Design And Duration Of Clinical Trials

These trials have so far invariably been randomized, double-blind,
placebo-controlled, parallel-arm studies. The period of double-blind
treatment has ranged from 3-6 months.

So far, the approval of drugs for the treatment of Alzheimer's Disease
has been based upon demonstrating efficacy in at least 2 such studies,
each of at least 3 months' duration.

### Outcome Measures For Assessing Drug Efficacy

Draft guidelines issued by this Agency have recommended that the
efficacy of putative drugs for dementia be determined using assessments
of the following as pre-specified co-primary outcome measures.

-   [Cognitive functions]{.underline}. The standardized test battery
    used most widely for this purpose is the Alzheimer's Disease
    Assessment Scale-Cognitive (ADAS-Cog). This battery assesses a
    spectrum of cognitive functions believed to be impaired in
    Alzheimer's Disease with each such function being allotted a maximum
    score; higher scores indicate more severe impairment. The total
    score for this battery can range from 0 (no impairment) to 70
    (severe impairment). Patients with Alzheimer's Disease decline on
    average 7 to 9 points on this scale every year, although this
    decline varies widely

-   [A clinician's overall impression of how the patient's cognition,
    behavior and function have changed over the course of the study;
    this has been referred to as a "global" assessment]{.underline}.
    Several different methods of making such an assessment have been
    proposed. The most widely used method is the Clinician Interview
    Based Impression of Change-Plus (CIBIC-Plus). The CIBIC-Plus is
    based upon information obtained from an interview of the patient and
    caregiver, and the recall of the patient's earlier condition, by an
    independent clinician who is blinded to the results of more formal
    assessments of cognitive function, such as the ADAS-Cog or
    Mini-Mental Status Examination, carried out by others. The
    CIBIC-Plus is rated on a scale from 1 (marked improvement) to 7
    (marked worsening); a rating of 4 denotes no change.

A cognitive rating scale has been recommended as a primary outcome
measure since the core symptoms of dementia are cognitive. However,
since the clinical significance of a change on a cognitive rating scale
may not be clear, a global scale has been recommended as a second
primary outcome measure. For approval to be granted it has been required
that superiority of the drug over placebo be demonstrated separately on
each of these 2 types of measures.

For most clinical trials completed over the last 10 years, the ADAS-Cog
and CIBIC-Plus have been the primary outcome measures.

### Symptomatic Effect Versus Disease Modification

The clinical trials on which the approval of drugs for Alzheimer's
Disease have been based have thus far been considered not to be designed
to distinguish between a purely symptomatic effect of the drug in
question and a disease-modifying effect. In this context, the term
"disease modifying" refers to an effect on the underlying pathology of
the disease.

Accordingly, the class labeling for these drugs states: "There is no
evidence that \-\-\-\-\-\--(name of drug) alters the course of the
underlying dementing process."

Two theoretical study designs that have been proposed for making this
distinction are further described below. Both designs apply to studies
that are randomized, double-blind, placebo-controlled and parallel-arm
throughout. Each proposed design has 2 study segments:

-   [Randomized withdrawal design]{.underline}. In the initial segment
    patients are randomized to either active drug or placebo. This
    segment is then allowed to continue for a sufficient duration to
    allow the active drug to demonstrate efficacy in relation to
    placebo. At the beginning of the second study segment those
    randomized to active drug in the initial phase are further
    randomized to either continue active drug or receive placebo. The
    second study segment then continues for an appropriate period. If at
    the end of the second segment, those receiving placebo, in that
    phase only, maintained their difference from those who received
    placebo through both segments, a disease-modifying effect would be
    assumed. On the other hand should those receiving placebo in the
    second segment only deteriorate to the level of those who received
    placebo throughout, a purely symptomatic effect would be inferred

-   [Randomized start design]{.underline}. In the initial segment
    patients are again randomized to active drug or placebo. This
    segment is then allowed to continue for a sufficient duration to
    allow the active drug to demonstrate efficacy in relation to
    placebo. At the end of that period those who received placebo during
    the initial segment are re-randomized to receive active drug or
    placebo for the entire duration of the second segment, as are those
    who initially received active drug. If at the end of the second
    segment the group which received placebo initially "catches up" with
    those who received active drug throughout a symptomatic effect is
    inferred; on the other hand if a difference between the groups is
    maintained, the active drug is assumed to have a disease-modifying
    effect

Both study designs can still be considered theoretical and have yet to
be adequately assessed in a clinical trial setting. The appropriate
durations of each segment, the frequency of assessments, and a number of
analytical issues need to be resolved.

The use of brain imaging measures (such as volumetric magnetic resonance
imaging of hippocampal and whole brain atrophy) have been proposed as
surrogate markers to assess the effects of putative disease-modifying
agents in Alzheimer's Disease. While a detailed review of regulatory
considerations that pertain to surrogate markers is beyond the scope of
this paper, it would be highly desirable for the following questions to
be answered prior to such a marker being considered acceptable for use
in key clinical trials that are intended to assess the effects of
disease-modifying agents in Alzheimer's Disease.

-   What clinical outcome is the imaging marker a surrogate for?

-   Does the imaging marker reliably predict the desired clinical
    outcome?

-   Is the desired clinical outcome based on the drug effect on the
    surrogate?

# Issues For Discussion

Drug trial protocols in MCI that have been reviewed by this Division
have had the following common features

-   All have been randomized, double-blind, placebo-controlled, and
    parallel-arm in design

-   Key selection criteria have consisted of the following

```{=html}
<!-- -->
```
-   Complaints of memory impairment, confirmed by objective testing
    using a standardized measure

-   Mild or no cognitive impairment (e.g., a Mini-Mental Status
    Examination score \> 24)

-   Preserved or only slightly impaired activities of daily living

-   A total score on the Clinical Dementia Rating scale (a structured
    measure of global function) of 0.5

-   Exclusion of depression based on scores on the Hamilton Depression
    Scale or similar measure

```{=html}
<!-- -->
```
-   Trials have been of 24-36 months' duration

-   Active drug treatment arms have had sample sizes between 240 and 650
    subjects

-   Key efficacy measures have consisted of

```{=html}
<!-- -->
```
-   Incidence or time to diagnosis of Alzheimer's Disease

-   Composite scores on a cognitive test battery

##  Can the entity be clearly defined in a clinical setting?

When a drug is approved by this Agency for treatment of a specific
entity, it is implied that there is broad agreement within the relevant
medical discipline(s) that

-   such an entity exists

-   is sufficiently homogenous

-   the condition can be identified by practicing clinicians with a
    reasonable degree of consistency using accepted operational criteria

In the case of MCI, a fundamental question is whether that entity is a
distinct clinical syndrome or a non-specific symptom complex
accompanying a variety of underlying pathologies. In deciding whether
MCI does represent a new distinct clinical syndrome, conventional
criteria for determining its clinical validity could be used. Such
criteria might include the following

-   The existence of a cluster of related symptoms with a characteristic
    time course, identified by cluster analysis or clinical observation,
    and

-   A distinct separation of the entity of interest from related
    conditions by discriminant function analysis.

It has been suggested that MCI can be distinguished clinically from a
reportedly much more common (if not universal) memory impairment
accompanying "normal" aging. Clinical terms that have been used over the
years to describe age-related cognitive impairment short of dementia
have included "benign senescent forgetfulness", "age-associated memory
impairment", "aging-associated cognitive decline", "aging-related
cognitive decline" and others. The nosological status of MCI in relation
to these other entities also warrants further discussion.

## Are there valid criteria for its diagnosis?

When clinical trials of a drug are conducted to evaluate its efficacy
for a specific indication, criteria should be available for defining
that entity so that a sufficiently homogenous population is selected for
such trials. Such criteria should ideally have a high degree of
sensitivity and specificity when compared with a "gold standard". While
the specific diagnostic criteria used in clinical trials may not always
be applicable in their entirety to the clinical setting, they should be
broadly representative of that entity as identified by a practicing
clinician.

For any set of diagnostic criteria that are being proposed for use in
clinical trials a high degree of inter-rater reliability is also
desirable.

In the case of the proposed entity of MCI, finding a gold standard may
however be problematical as such a standard does not appear to exist.
Whereas the sensitivity and specificity of the NINCDS-ADRDA criteria for
probable Alzheimer's Disease have been compared against the
histopathological diagnosis as the gold standard, such an approach does
not seem practical in MCI even if the pathological substrate of that
entity could be clearly defined.

Instead of determining the sensitivity and specificity of a set of
diagnostic criteria for MCI, assuming that the existence of that entity
is valid, against a non-existent gold standard, the appropriateness of
such criteria for use in clinical trials could conceivably be determined
based on whether or not they are sufficiently predictive of an outcome
that an intervention is intended to counter. For example, if the
prevention of overt Alzheimer's Disease is the desired outcome of such
an intervention, diagnostic criteria for MCI that are reasonably
predictive of the subsequent development of Alzheimer's Disease could be
used to select patients for such a study. Such an approach to validating
the diagnosis would require a robust experience of the longitudinal
course of MCI.

The use of diagnostic criteria for MCI that are highly predictive of the
subsequent development of Alzheimer's Disease, however, makes it even
more likely that those defined as having MCI by such criteria may have
an early stage of Alzheimer's Disease (see Section 2.3).

It has also been suggested that diagnostic criteria for MCI that are
based on clinical and neuropsychological assessments, could be further
refined so as to be more predictive of the development of subsequent
Alzheimer's Disease by using genotyping, cerebrospinal fluid biomarkers,
and brain imaging. However, if such a population can be defined only
with the aid of relatively sophisticated diagnostic techniques that may
not be widely available, the applicability of efficacy data from such
clinical trials to routine clinical practice may also be questionable.

## Does Mild Cognitive Impairment merely represent an early stage of Alzheimer\'s Disease in a significant proportion of those with the former condition? 

This is a critical issue in regard to whether the putative entity of MCI
justifies a claim that is distinct from that already granted by this
Agency to the sponsors of tacrine, donepezil, and rivastigmine. The
claim for those 3 drugs is for "treatment of mild-to-moderate dementia
of the Alzheimer's type."

As noted earlier, the approved claims for tacrine, donepezil, and
rivastigmine have been based upon studies carried out in patients with
probable Alzheimer's Disease, as defined by the NINCDS-ADRDA criteria.
In essence these criteria require the presence of progressive
deterioration in 2 or more cognitive domains, and the absence of
disturbances of consciousness, or of any other systemic or brain
disorder that could explain the patient's cognitive impairment.

There appears to be some evidence that MCI, as that proposed entity is
currently viewed, may, at least in a substantial proportion of such a
population, be an early stage of Alzheimer's Disease that is not yet
advanced enough to satisfy the NINCDS-ADRDA criteria for diagnosing that
entity.

-   Several prospective studies have suggested that a significant
    proportion of those with so-called MCI will develop full-fledged
    Alzheimer's Disease if observed for a sufficient period of time.

-   An isolated decline in memory, especially verbal episodic memory,
    which is considered by some to be the sine qua non of Mild Cognitive
    Impairment, is also considered to be a common early sign of
    Alzheimer's Disease

-   The limited contemporaneous autopsy data that is available for those
    diagnosed to have MCI appears to indicate that a number of these
    individuals have histopathological changes in the brain that are
    qualitatively similar to those of Alzheimer's Disease, even if they
    are quantitatively less-pronounced.

-   Brain imaging (CT, MRI and SPECT) shows abnormalities in those
    diagnosed to have MCI that are similar in quality and location to
    those seen in Alzheimer's Disease, although such abnormalities may
    be quantitatively less pronounced.

It further could seem logical that if the objective of clinical drug
trials in MCI is to prevent or delay the development of overt
Alzheimer's Disease, then, at least in theory, it is being assumed that
such drugs are treating an earlier stage in the pathogenesis of the
latter condition.

If MCI is to a large extent the same as early Alzheimer's Disease,
pathologically and pathophysiologically, and if a drug can be
demonstrated to have efficacy, however that is determined, in treating
MCI, in what way would such a claim differ from one for mild Alzheimer's
Disease (that satisfies the NINCDS-ADRDA criteria)? The Division has to
date adopted the view that a separate claim for MCI distinct from that
for Alzheimer's Disease may not be justified.

If Mild Cognitive Impairment is not, in large measure, an early form of
Alzheimer's Disease, but merely a manifestation of a variety of
underlying diseases, then the issue that needs to be addressed is
whether Mild Cognitive Impairment is sufficiently homogenous to justify
a separate claim.

## Mild Cognitive Impairment as a non-specific symptom of a variety of underlying diseases

## As noted above, it is possible that the entity called MCI by some is (if not early Alzheimer's Disease or another specific clinical entity) a symptom, or symptom complex, common to a number of other illnesses, (analogous to fever or pain, which can occur in the setting of a number of conditions). Ordinarily, in such a case, the Agency grants a claim for a drug as a treatment for the symptom, but only after a showing that the drug effectively treats the symptom in a representative number of clinical settings in which it occurs (for example, the Agency will grant a claim for a drug as an analgesic once it is shown that the treatment is effective in treating dental pain, surgical pain, muscle contraction headache, etc.). Of course, it is possible that a treatment may be approved for a "symptom" in a particular clinical setting, even though the "symptom" appears to occur in multiple settings (as noted earlier, a claim for the excessive daytime sleepiness of narcolepsy would be an example of such a claim). However, in these cases, the sponsor must ordinarily show that the treatment is ineffective against that symptom in the other clinical settings in which it appears to occur, or present other evidence (pathophysiologic, etc.) that the symptom in the sought after clinical setting is specific to that setting, even though it may appear to be identical clinically to a symptom seen in other clinical settings. {#as-noted-above-it-is-possible-that-the-entity-called-mci-by-some-is-if-not-early-alzheimers-disease-or-another-specific-clinical-entity-a-symptom-or-symptom-complex-common-to-a-number-of-other-illnesses-analogous-to-fever-or-pain-which-can-occur-in-the-setting-of-a-number-of-conditions.-ordinarily-in-such-a-case-the-agency-grants-a-claim-for-a-drug-as-a-treatment-for-the-symptom-but-only-after-a-showing-that-the-drug-effectively-treats-the-symptom-in-a-representative-number-of-clinical-settings-in-which-it-occurs-for-example-the-agency-will-grant-a-claim-for-a-drug-as-an-analgesic-once-it-is-shown-that-the-treatment-is-effective-in-treating-dental-pain-surgical-pain-muscle-contraction-headache-etc..-of-course-it-is-possible-that-a-treatment-may-be-approved-for-a-symptom-in-a-particular-clinical-setting-even-though-the-symptom-appears-to-occur-in-multiple-settings-as-noted-earlier-a-claim-for-the-excessive-daytime-sleepiness-of-narcolepsy-would-be-an-example-of-such-a-claim.-however-in-these-cases-the-sponsor-must-ordinarily-show-that-the-treatment-is-ineffective-against-that-symptom-in-the-other-clinical-settings-in-which-it-appears-to-occur-or-present-other-evidence-pathophysiologic-etc.-that-the-symptom-in-the-sought-after-clinical-setting-is-specific-to-that-setting-even-though-it-may-appear-to-be-identical-clinically-to-a-symptom-seen-in-other-clinical-settings. .unnumbered}

## Failure to demonstrate the specificity of the symptom to the clinical setting in the latter case can give rise to a so-called pseudospecific claim, which arises as an artifact of the population studied, and can be misleading. For example, if a sponsor studied the effects of their drug only in Alzheimer's patients with headache, and showed the treatment to be effective against the headache in these patients, they would not be entitled to a claim for their drug as a treatment for headache in patients with Alzheimer's Disease. Such a claim would be pseudospecific, in that it arises entirely from the fact that the sponsor chose to study only Alzheimer's Disease patients with headache. Unless the sponsor could present compelling evidence that the headaches treated were specific to Alzheimer's Disease, and that the drug differentially treats such headaches, such a claim would be considered misleading, and would be unacceptable.  {#failure-to-demonstrate-the-specificity-of-the-symptom-to-the-clinical-setting-in-the-latter-case-can-give-rise-to-a-so-called-pseudospecific-claim-which-arises-as-an-artifact-of-the-population-studied-and-can-be-misleading.-for-example-if-a-sponsor-studied-the-effects-of-their-drug-only-in-alzheimers-patients-with-headache-and-showed-the-treatment-to-be-effective-against-the-headache-in-these-patients-they-would-not-be-entitled-to-a-claim-for-their-drug-as-a-treatment-for-headache-in-patients-with-alzheimers-disease.-such-a-claim-would-be-pseudospecific-in-that-it-arises-entirely-from-the-fact-that-the-sponsor-chose-to-study-only-alzheimers-disease-patients-with-headache.-unless-the-sponsor-could-present-compelling-evidence-that-the-headaches-treated-were-specific-to-alzheimers-disease-and-that-the-drug-differentially-treats-such-headaches-such-a-claim-would-be-considered-misleading-and-would-be-unacceptable. .unnumbered}

It will be important for the Committee to discuss the possibility that
MCI is a non-specific symptom of several underlying pathologies, and, if
it is, what an appropriate development program for such a symptom might
be.

##  What outcome measures are appropriate to use in clinical drug trials conducted in Mild Cognitive Impairment? Should clinical drug trials in Mild Cognitive Impairment incorporate any special features in their design?

If it can be assumed that Mild Cognitive Impairment is a distinct
clinical syndrome, and that there are widely accepted and validated
criteria for its diagnosis, a number of further questions arise as to
the design and conduct of such trials.

One such issue is what key outcome measure(s) should be used in clinical
trials for that entity. The few protocols that we have reviewed so far
have used the incidence, or time to diagnosis, of overt Alzheimer's
Disease (using the NINCDS-ADRDA or similar criteria) as a primary
outcome measure, supplemented in at least one instance by a composite
score on a cognitive measure. However as already indicated in Section
2.3, if the clinical diagnosis of Alzheimer's Disease is to be the
primary endpoint in such studies, and if on that basis the drug is shown
to be effective, it could be argued that the drug is in fact treating an
earlier stage of Alzheimer's Disease that is, at the time of study
entry, not sufficiently advanced to satisfy the NINCDS-ADRDA criteria.

In this case, preventing (or delaying the time to diagnosis of) AD might
be considered an inappropriate claim, first, because it might be
interpreted to imply an effect on the underlying pathology of the
disease, and second, because the effect would really be an effect on the
symptoms of AD (the indication for which the current drugs are
approved); the delaying of the time to diagnosis of AD would merely be
an artifact of our inability to diagnose AD earlier in its course, and
would inappropriately imply that MCI is fundamentally different from AD.

A further issue concerns the appropriate sample size and duration for
such studies; unless data from completed studies are available, such
estimates will be need to be based upon what is known about the natural
history of Mild Cognitive Impairment and what would be considered a
desirable clinical effect.

Protocols for Mild Cognitive Impairment that have come to the attention
of this Division have not been designed so as to distinguish between
symptomatic and disease-modifying effects of the study drugs that have
been proposed for use. Whether designs similar to those proposed for
overt Alzheimer's Disease (see Section 1.4.5) are applicable to Mild
Cognitive Impairment is unclear.

The use of brain imaging (most specifically, volumetric magnetic
resonance imaging of hippocampal and whole brain atrophy) has been
proposed as a surrogate marker to assess the effects of putative
disease-modifying agents in MCI. For a brief regulatory perspective on
surrogate markers, please see Section 1.4.5. In clinical protocols that
this Division has seen, volumetric magnetic resonance imaging has been
proposed as a measure for use only in a small proportion of the study
centers enrolled.

In this memo, we have outlined the issues we would like the Committee to
discuss in advising the Division about the development of treatments for
the symptom complex currently referred to by some as MCI. Of course, we
are eager to hear your views not only on the issues we have identified,
but on any other issue you believe to be relevant. We very much
appreciate your thoughts on this matter, and look forward to seeing you
and to a lively discussion.