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Journal of Parkinson’s Disease 4 (2014) 585–589
DOI 10.3233/JPD-140385
IOS Press
585
Research Report
Therapeutic Development Paths for
Cognitive Impairment in Parkinson’s
Disease: Report of a Regulatory Roundtable
Jamie Eberlinga,∗
, Lona Vincenta
, Jennifer G. Goldmanb
, Daniel Weintraubc
, Jaime Kulisevskyd
,
Connie Marrase
, Glenn Stebbinsb
and Karl Kieburtzf
aMichael J. Fox Foundation for Parkinson’s Research, New York, NY, USA
bRush University Medical Center, Chicago, IL, USA
cUniversity of Pennsylvania, Philadelphia, PA, USA
dSant Pau Hospital, Barcelona, Spain
eUniversity of Toronto, Toronto, Canada
fUniversity of Rochester, Rochester, NY, USA
Abstract. Cognitive impairment is a common occurrence in Parkinson’s disease (PD), although the severity and specific pre-
sentation varies across patients. Initial deficits, including mild cognitive impairment (PD-MCI), may remain stable or in many
cases, may progress over variable lengths of time to Parkinson’s disease dementia (PDD). As there are currently no marketed
treatments for milder forms of cognitive impairment, an opportunity exists to define the path for therapeutic development in
this area. In the absence of a well-defined path for the approval of therapies that target PD-MCI, pharmaceutical companies are
unlikely to pursue this indication. In order to move forward and improve the quality of life for PD patients, it is imperative for
the field to have consensus on the definition of PD-MCI, the best instruments to measure cognitive decline, and a strategy for
future clinical trials.
Keywords: Parkinson’s, cognition, FDA, clinical trial
As an initial approach to address existing obsta-
cles and gather the perspective of thought leaders in
the field, in April 2013 the Michael J. Fox Foun-
dation for Parkinson’s Research (MJFF) organized
the “Regulatory Roundtable for Cognitive Impair-
ment in PD”. In attendance were representatives from
MJFF, industry, the Alzheimer’s disease (AD) commu-
nity, International Parkinson and Movement Disorders
Society (IPMDS; formerly the Movement Disorders
Society (MDS)), National Institute for Neurological
Disorders and Stroke (NINDS), Parkinson’s Action
Network (PAN), Parkinson’s Progression Markers Ini-
tiative (PPMI), Coalition Against Major Diseases
∗Correspondence to: JamieEberling,PhD,498SeventhAve,18th
Floor, New York, NY 10018, USA. Tel.: +1 212 509 0995/Ext. 278;
E-mail: JEberling@michaeljfox.org.
(CAMD), 16 representatives from the U.S. Food and
Drug Administration (FDA), and key opinion leaders
on cognitive impairment in PD. The goal of the meet-
ing was to identify the regulatory requirements for
pursuing a therapeutic indication for cognitive impair-
ment in PD, focusing on pre-dementia stages. The
discussion concentrated on the diagnostic criteria for
PD-MCI, existing assessment and outcome measures,
and short-term and long-term strategies for therapeutic
development.
DEFINING AND DIAGNOSING PD-MCI
Estimating the prevalence of PD-MCI has been
challenging due to the heterogeneous criteria used
to diagnose and define the condition. Recent reviews
ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
586 J. Eberling et al. / Therapeutic Development Paths for PD-MCI
report a mean prevalence of 27%, ranging from 19%
to 38% [1]. To aid in defining the condition, the recent
publication of MDS PD-MCI diagnostic criteria pro-
videauniformdefinitionofPD-MCIthatcanbereadily
used in both clinical and research settings. A com-
mon definition of PD-MCI to be utilized by patients,
clinicians, and researchers is necessary to help iden-
tify the clinical characteristics of PD-MCI, the best
predictors of conversion to PDD, and the effects of
PD-MCI on quality of life and daily functioning. In
addition, a uniform definition is critical for defining
patient populations for inclusion in research studies,
and for allowing clinicians, researchers, and patients
and caregivers to communicate among each other and
across settings. These criteria aim to define a group
of PD patients who report cognitive decline compared
with their premorbid state, exhibit cognitive deficits
based on normative data, but do not have functional
deficits significant enough to meet criteria for PDD.
For many patients, the exact percentage of whom still
needs to be determined, the “MCI” stage may repre-
sent a transitional point between normal cognition and
dementia,andthusapotentialharbingerofPDD.While
many patients with PD-MCI convert to dementia, PD-
MCI may have a variable course such that for some
patients, it remains a rather static condition, while in
others, follow-up testing demonstrates improvement
[2, 3]. Determining the factors that govern this hetero-
geneity nature and course of PD-MCI, including its
different subtypes, will be important factors in devel-
oping therapeutic interventions and designing clinical
trials in PD-MCI [4–6].
The MDS PD-MCI diagnostic criteria represent a
valuable tool for clinical practice and provide a uni-
form definition of the clinical syndrome, but are being,
and continue to need to be, applied and validated in
a range of clinical and research settings. Operational
issues such as how to elicit and define a decline in cog-
nitive ability from the patient or informant, and what a
level of subtle functional impairment related to cogni-
tive changes is acceptable to still fulfill criteria for MCI
(rather than dementia) still need to be defined in order
to ensure that a clearly-defined population is being
studied. While a ‘subjective complaint’ by the patient
or informant was a cornerstone of early MCI criteria
[7], this aspect is less critical in the MDS PD-MCI cri-
teria as decline observed by the clinician can suffice.
Methods to elicit cognitive complaints are discussed
in Marras et al. [8]. Measurement strategies for func-
tional impairment are discussed in more detail below,
and will be a key aspect of demonstrating therapeu-
tic efficacy. From the regulatory perspective, it is the
opinion of the authors that the FDA may be willing to
consider an indication of PD-MCI without reference to
the underlying neurobiological substrate, as was done
when recognizing PDD in the context of approval for
rivastigmine. This implies that clinical testing and tri-
als can be initiated while the field pursues additional
research on defining PD-MCI. This also implies that
though having standardized diagnostic criteria will be
valuable for clinical research, to receive drug approval
sponsors will only be required to demonstrate that
their patient population has a cognitive deficit, whether
proven related to the underlying PD or not, and that this
deficit is improved by the therapy under development.
ASSESSING PD-MCI – COGNITION
SCALES
Successful clinical trials depend on outcome mea-
sures that are able to accurately reflect change in
cognition due to the therapeutic agent or interven-
tion. For some time it has been recognized that
frequently used global cognitive instruments, such as
the Mini-Mental State Examination (MMSE) [9] and
the Alzheimer’s Disease Assessment Scale-cognitive
subscale (ADAS-cog), [10] do not map well onto
the mild cognitive deficits reported to occur in many
PD patients due to their focus on “cortical” deficits
and their development for non-PD populations. As
a result, several global cognitive assessment instru-
ments have been developed or undergone validation
for use in PD, including the Parkinson’s Disease-
Cognitive Rating Scale (PD-CRS), [11] the Parkinson
Neuropsychometric Dementia Assessment (PANDA),
[12] the Scales for Outcomes of Parkinson’s Disease-
Cognition (SCOPA-COG), [13] the Dementia Rating
Scale-2 (DRS-2), [14] and the Montreal Cognitive
Assessment (MoCA) [15, 16]. In addition, a plethora of
individual neuropsychological tests have been used in
PD to specifically assess executive, memory, attention,
visuospatial and language domain abilities, often in
different combinations to create a battery of tests. This
heterogeneity of neuropsychological tests and batter-
ies used in many studies of PD cognitive impairment
has been another challenge in assessing PD-MCI.
All of the existing instruments have limitations, and
none (other than the MoCA for screening purposes)
has yet gained wide acceptance. In the short term, the
FDA indicated that sponsors should focus on selecting
the scale or domain that is most appropriate for the
trial design and sample population and that they are
not endorsing any particular scale for use in PD-MCI
J. Eberling et al. / Therapeutic Development Paths for PD-MCI 587
trials. This is consistent with the methodology of the
MDS PD-MCI diagnostic criteria, which allows the
cognitive evaluation to be conducted with a number of
existing instruments. Though the case can be made that
there remains a need for a consensus-driven neuropsy-
chological assessment battery that is sensitive to early
cognitive decline in PD and appropriate for use in all
aspects of clinical research, more research is needed
to probe the practicability of existing instruments in
multicenter research before the field makes an invest-
ment in a new battery. In particular, there is a need for
studies that assess the sensitivity of the various scales
to change over time and in response to treatment. This
type of information will be critical for trial design and
power calculations but currently there are not enough
data to know which PD-specific scales will be most
effective.
ASSESSING PD-MCI – THE ROLE OF
FUNCTIONAL IMPAIRMENT
The FDA indicated that they will require evidence
of functional benefit in trials for PD-MCI. This will
likely entail that a functional scale be used as a co-
primary outcome to document that cognitive changes
associated with an investigational drug are clinically
relevant. Cognitive deficits identified in PD subjects
diagnosed with PD-MCI may interfere significantly
with their ability to implement higher-level instrumen-
tal activities of daily living (IADLs), although not as
significantly as in PDD [17–19]. Functional decline
may be assessed using generic activities of daily living
(ADL) instruments that are commonly used in AD tri-
als (e.g., the ADCS-ADL). However, PD-related motor
impairment potentially biases the rating of some activi-
ties, [20] and the different cognitive profile of PD (e.g.,
more executive deficits than in AD) limit the utility and
sensitivity of the AD-designed instruments [21].
There are two PD-specific functional instruments
that have been developed to measure the impact of
cognitive impairment. The PD-Cognitive Functional
Rating Scale (PD-CFRS) is a validated and reliable 5-
minute questionnaire of 12 items that captures relevant
functional changes related to early and late cogni-
tive impairment in PD. It has shown good correlations
with neuropsychological ratings and good capacity to
detect meaningful changes over time. The Brief Penn
Daily Activities Questionnaire (PDAQ), [22] a 15-item
scale administered to knowledgeable informants, was
designed to assess IADLs sensitive and specific to cog-
nitiveimpairmentinPD.Stillunpublished,preliminary
results from the validation process show that the PDAQ
present good discriminative validity across stages of
cognitive impairment. Additional studies are needed
to determine if one or both of these functional scales
could be useful for PD-MCI trials.
PLANNING FOR CLINICAL TRIALS
The design of clinical trials that are intended to mea-
sureshort-termchangesincognitivefunctionshouldbe
relatively simple; standard, parallel group or crossover
designs. The latter may be particularly appealing in
early, learning phase trials, because of the reduc-
tion in variability (which allows much smaller sample
sizes) due to within-subject comparisons. Crossover
designs have their own challenges (e.g., loss to fol-
low up, sequence effects), but may still be useful in
the early evaluation of agents intended to improve
cognitive performance. On the other hand, assessing
long-term change in cognitive performance, such as
slowing cognitive decline or preventing the onset of
dementia (i.e., disease-modifying effects), present a
major design challenge, and biomarkers could play
a critical role in such studies. It is premature to rec-
ommend specific biomarkers but ongoing research
should help to determine those that are most useful and
could include imaging (positron emission tomography
and fluorodeoxyglucose, functional MRI, amyloid,
and hopefully eventually alpha-synuclein) and cere-
brospinal fluid, blood and genetic markers, the subject
of a recent review [23]. As disentangling short-term
improvements from long-term effects is difficult, a
two-period design (e.g., delayed start or washout) can
be considered. There are many inherent complexities
in such designs (as seen with the ADAGIO study), [24]
including the duration of the two study periods, avoid-
ing dropouts, and methods to analyze the stability of
differences observed at study completion. An attractive
alternative may be a survival analysis, such as delay
of time to onset of dementia or cognitive impairment.
The main challenge of such ‘survival’ studies will be a
rigorous, yet pragmatic, definition of these endpoints.
Given the novel nature of this therapeutic endpoint,
discussions of trial design with regulatory authorities
in advance of the study will be essential.
THE CURRENT THERAPEUTIC
LANDSCAPE
Many of the therapeutics that have been tested for
PD-MCI and PDD are those that have been tested
588 J. Eberling et al. / Therapeutic Development Paths for PD-MCI
Box 1. Path Forward for Cognitive Impairment in PD
General Path Forward
• The FDA is open to an indication for mild cognitive impairment in PD
• For regulatory consideration, it may be appropriate to pursue a PD-MCI indication without reference to the underlying cause of
impairment
• Drug approvals for an indication of PD-MCI will likely require a co-primary measure (a cognitive outcome measure and a functional
measure)
Short Term Path: Long Term Path:
For immediate drug development using existing scales and diagnostic
criteria
Includes efforts to validate diagnostic criteria and/or create new
instruments
Diagnostic Criteria Diagnostic Criteria
• Current MDS PD-MCI diagnostic criteria can be used to identify a
patient population for clinical testing
• If a sponsor chooses not to use the criteria, they must demonstrate that
the study participants have a cognitive deficit
• MDS will work to validate and modify the PD-MCI diagnostic
criteria (where needed) so the field can have a standardized
approach for identifying and classifying study participants
Outcome Measures Outcome Measures
• Existing cognitive scales are sufficient for use in clinical trials on
PD-MCI
• Sponsors should select the outcome measure/scale most likely to
demonstrate change in the patient population
• The scale does not have to be specific to Parkinson’s nor does it need to
be an established measure of response to treatment
• The field should work at analyzing PD-MCI datasets across a
number of research studies in order to identify the scale items
and domains most sensitive to change
• If the existing scale instruments, either cognitive of functional,
prove to be sub-optimal in clinical testing, the PD field could
develop a new scale or a composite measure
• In addition to a cognitive scales, sponsors will be required to include a
measure of function to demonstrate clinical meaningfulness
Biomarkers
• The field should work toward the development of an imaging,
fluid, or combination biomarker
for MCI and AD, including cholinesterase inhibitors
and memantine. This seems a reasonable strategy
given the overlap in many of the cognitive symptoms
although to date rivastigmine is the only approved
drug for PDD, albeit modestly effective. Thera-
peutics currently being tested for PD-MCI include
rasagiline, rivastigmine, droxidopa, and AVE8112, a
PDE4 inhibitor (see clinicaltrials.gov NCT01723228,
NCT01519271, NCT02066571, NCT01803945). In
addition to pharmacological interventions, nonphar-
macolocial interventions such as cognitive training,
exercise programs, and brain stimulation techniques
are being explored [25–27]. While this is a growing
area of research there is a need for rigorous studies with
appropriate control groups to definitively test these
approaches. A clear regulatory path with established
diagnostic criteria and outcome measures would likely
increase interest in developing PD-MCI therapies.
THE PATH FORWARD
The pursuit of disease-modifying therapies for neu-
rological diseases, including PD, is the ultimate goal
for drug developers in this therapeutic space, but the
regulatory requirements for FDA approval and the
expense and complexities of such clinical trials rep-
resent very high hurdles. Given the challenges in
pursuing a disease-modifying approach for cognitive
impairment, symptomatic therapies may represent an
attractive way to move the path forward for drug devel-
opment in PD-MCI at this point, and some of these may
also prove to delay the time from PD-MCI to dementia.
Symptomatic trials could be advantageous given their
shorter duration compared with disease-modifying tri-
als. Disease-modifying therapies, albeit likely more
challenging to develop since requiring longer trials
and more complicated study designs, remain the “holy
grail”, as they have the potential to impact on disease
course. Slowing the progression of cognitive decline
and thus forestalling or preventing the development
of dementia would represent a tremendous advance in
the management of patients with PD. The challenges
posed do not mean that disease modification is not
worth pursuing, but rather that symptomatic therapies
may represent an easier initial target for advances in
PD-MCI treatments.
The good news is that there is a path forward for
therapeutic development for cognitive impairment in
PD, though this path will likely continue to be mod-
ified as we advance our understanding of PD-MCI as
a syndrome. In pursuit of drug development or clini-
cal testing, the field will need to address the following
challenges: [1] refining and validating the diagnostic
criteria in order to identify the patients who are most
likely to benefit from treatment, [2] understanding the
prognostic significance of PD-MCI, including the tra-
jectory of cognitive decline, [3] further developing cur-
rent instruments, including those to measure functional
J. Eberling et al. / Therapeutic Development Paths for PD-MCI 589
impairment, and [4] discovering and validating cogni-
tion biomarkers, which likely will be critical for patient
selection for clinical trials, as well as for objective and
sensitive measures of change in cognition over time.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
The views expressed in this manuscript are solely
those of the authors and do not represent any for-
mal guidance from the Food and Drug Administration
(FDA).
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Therapeutic Development Paths for Cognitive Impairment in Parkinson's Disease: Report of a Regulatory Roundtable

  • 1. Journal of Parkinson’s Disease 4 (2014) 585–589 DOI 10.3233/JPD-140385 IOS Press 585 Research Report Therapeutic Development Paths for Cognitive Impairment in Parkinson’s Disease: Report of a Regulatory Roundtable Jamie Eberlinga,∗ , Lona Vincenta , Jennifer G. Goldmanb , Daniel Weintraubc , Jaime Kulisevskyd , Connie Marrase , Glenn Stebbinsb and Karl Kieburtzf aMichael J. Fox Foundation for Parkinson’s Research, New York, NY, USA bRush University Medical Center, Chicago, IL, USA cUniversity of Pennsylvania, Philadelphia, PA, USA dSant Pau Hospital, Barcelona, Spain eUniversity of Toronto, Toronto, Canada fUniversity of Rochester, Rochester, NY, USA Abstract. Cognitive impairment is a common occurrence in Parkinson’s disease (PD), although the severity and specific pre- sentation varies across patients. Initial deficits, including mild cognitive impairment (PD-MCI), may remain stable or in many cases, may progress over variable lengths of time to Parkinson’s disease dementia (PDD). As there are currently no marketed treatments for milder forms of cognitive impairment, an opportunity exists to define the path for therapeutic development in this area. In the absence of a well-defined path for the approval of therapies that target PD-MCI, pharmaceutical companies are unlikely to pursue this indication. In order to move forward and improve the quality of life for PD patients, it is imperative for the field to have consensus on the definition of PD-MCI, the best instruments to measure cognitive decline, and a strategy for future clinical trials. Keywords: Parkinson’s, cognition, FDA, clinical trial As an initial approach to address existing obsta- cles and gather the perspective of thought leaders in the field, in April 2013 the Michael J. Fox Foun- dation for Parkinson’s Research (MJFF) organized the “Regulatory Roundtable for Cognitive Impair- ment in PD”. In attendance were representatives from MJFF, industry, the Alzheimer’s disease (AD) commu- nity, International Parkinson and Movement Disorders Society (IPMDS; formerly the Movement Disorders Society (MDS)), National Institute for Neurological Disorders and Stroke (NINDS), Parkinson’s Action Network (PAN), Parkinson’s Progression Markers Ini- tiative (PPMI), Coalition Against Major Diseases ∗Correspondence to: JamieEberling,PhD,498SeventhAve,18th Floor, New York, NY 10018, USA. Tel.: +1 212 509 0995/Ext. 278; E-mail: JEberling@michaeljfox.org. (CAMD), 16 representatives from the U.S. Food and Drug Administration (FDA), and key opinion leaders on cognitive impairment in PD. The goal of the meet- ing was to identify the regulatory requirements for pursuing a therapeutic indication for cognitive impair- ment in PD, focusing on pre-dementia stages. The discussion concentrated on the diagnostic criteria for PD-MCI, existing assessment and outcome measures, and short-term and long-term strategies for therapeutic development. DEFINING AND DIAGNOSING PD-MCI Estimating the prevalence of PD-MCI has been challenging due to the heterogeneous criteria used to diagnose and define the condition. Recent reviews ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
  • 2. 586 J. Eberling et al. / Therapeutic Development Paths for PD-MCI report a mean prevalence of 27%, ranging from 19% to 38% [1]. To aid in defining the condition, the recent publication of MDS PD-MCI diagnostic criteria pro- videauniformdefinitionofPD-MCIthatcanbereadily used in both clinical and research settings. A com- mon definition of PD-MCI to be utilized by patients, clinicians, and researchers is necessary to help iden- tify the clinical characteristics of PD-MCI, the best predictors of conversion to PDD, and the effects of PD-MCI on quality of life and daily functioning. In addition, a uniform definition is critical for defining patient populations for inclusion in research studies, and for allowing clinicians, researchers, and patients and caregivers to communicate among each other and across settings. These criteria aim to define a group of PD patients who report cognitive decline compared with their premorbid state, exhibit cognitive deficits based on normative data, but do not have functional deficits significant enough to meet criteria for PDD. For many patients, the exact percentage of whom still needs to be determined, the “MCI” stage may repre- sent a transitional point between normal cognition and dementia,andthusapotentialharbingerofPDD.While many patients with PD-MCI convert to dementia, PD- MCI may have a variable course such that for some patients, it remains a rather static condition, while in others, follow-up testing demonstrates improvement [2, 3]. Determining the factors that govern this hetero- geneity nature and course of PD-MCI, including its different subtypes, will be important factors in devel- oping therapeutic interventions and designing clinical trials in PD-MCI [4–6]. The MDS PD-MCI diagnostic criteria represent a valuable tool for clinical practice and provide a uni- form definition of the clinical syndrome, but are being, and continue to need to be, applied and validated in a range of clinical and research settings. Operational issues such as how to elicit and define a decline in cog- nitive ability from the patient or informant, and what a level of subtle functional impairment related to cogni- tive changes is acceptable to still fulfill criteria for MCI (rather than dementia) still need to be defined in order to ensure that a clearly-defined population is being studied. While a ‘subjective complaint’ by the patient or informant was a cornerstone of early MCI criteria [7], this aspect is less critical in the MDS PD-MCI cri- teria as decline observed by the clinician can suffice. Methods to elicit cognitive complaints are discussed in Marras et al. [8]. Measurement strategies for func- tional impairment are discussed in more detail below, and will be a key aspect of demonstrating therapeu- tic efficacy. From the regulatory perspective, it is the opinion of the authors that the FDA may be willing to consider an indication of PD-MCI without reference to the underlying neurobiological substrate, as was done when recognizing PDD in the context of approval for rivastigmine. This implies that clinical testing and tri- als can be initiated while the field pursues additional research on defining PD-MCI. This also implies that though having standardized diagnostic criteria will be valuable for clinical research, to receive drug approval sponsors will only be required to demonstrate that their patient population has a cognitive deficit, whether proven related to the underlying PD or not, and that this deficit is improved by the therapy under development. ASSESSING PD-MCI – COGNITION SCALES Successful clinical trials depend on outcome mea- sures that are able to accurately reflect change in cognition due to the therapeutic agent or interven- tion. For some time it has been recognized that frequently used global cognitive instruments, such as the Mini-Mental State Examination (MMSE) [9] and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), [10] do not map well onto the mild cognitive deficits reported to occur in many PD patients due to their focus on “cortical” deficits and their development for non-PD populations. As a result, several global cognitive assessment instru- ments have been developed or undergone validation for use in PD, including the Parkinson’s Disease- Cognitive Rating Scale (PD-CRS), [11] the Parkinson Neuropsychometric Dementia Assessment (PANDA), [12] the Scales for Outcomes of Parkinson’s Disease- Cognition (SCOPA-COG), [13] the Dementia Rating Scale-2 (DRS-2), [14] and the Montreal Cognitive Assessment (MoCA) [15, 16]. In addition, a plethora of individual neuropsychological tests have been used in PD to specifically assess executive, memory, attention, visuospatial and language domain abilities, often in different combinations to create a battery of tests. This heterogeneity of neuropsychological tests and batter- ies used in many studies of PD cognitive impairment has been another challenge in assessing PD-MCI. All of the existing instruments have limitations, and none (other than the MoCA for screening purposes) has yet gained wide acceptance. In the short term, the FDA indicated that sponsors should focus on selecting the scale or domain that is most appropriate for the trial design and sample population and that they are not endorsing any particular scale for use in PD-MCI
  • 3. J. Eberling et al. / Therapeutic Development Paths for PD-MCI 587 trials. This is consistent with the methodology of the MDS PD-MCI diagnostic criteria, which allows the cognitive evaluation to be conducted with a number of existing instruments. Though the case can be made that there remains a need for a consensus-driven neuropsy- chological assessment battery that is sensitive to early cognitive decline in PD and appropriate for use in all aspects of clinical research, more research is needed to probe the practicability of existing instruments in multicenter research before the field makes an invest- ment in a new battery. In particular, there is a need for studies that assess the sensitivity of the various scales to change over time and in response to treatment. This type of information will be critical for trial design and power calculations but currently there are not enough data to know which PD-specific scales will be most effective. ASSESSING PD-MCI – THE ROLE OF FUNCTIONAL IMPAIRMENT The FDA indicated that they will require evidence of functional benefit in trials for PD-MCI. This will likely entail that a functional scale be used as a co- primary outcome to document that cognitive changes associated with an investigational drug are clinically relevant. Cognitive deficits identified in PD subjects diagnosed with PD-MCI may interfere significantly with their ability to implement higher-level instrumen- tal activities of daily living (IADLs), although not as significantly as in PDD [17–19]. Functional decline may be assessed using generic activities of daily living (ADL) instruments that are commonly used in AD tri- als (e.g., the ADCS-ADL). However, PD-related motor impairment potentially biases the rating of some activi- ties, [20] and the different cognitive profile of PD (e.g., more executive deficits than in AD) limit the utility and sensitivity of the AD-designed instruments [21]. There are two PD-specific functional instruments that have been developed to measure the impact of cognitive impairment. The PD-Cognitive Functional Rating Scale (PD-CFRS) is a validated and reliable 5- minute questionnaire of 12 items that captures relevant functional changes related to early and late cogni- tive impairment in PD. It has shown good correlations with neuropsychological ratings and good capacity to detect meaningful changes over time. The Brief Penn Daily Activities Questionnaire (PDAQ), [22] a 15-item scale administered to knowledgeable informants, was designed to assess IADLs sensitive and specific to cog- nitiveimpairmentinPD.Stillunpublished,preliminary results from the validation process show that the PDAQ present good discriminative validity across stages of cognitive impairment. Additional studies are needed to determine if one or both of these functional scales could be useful for PD-MCI trials. PLANNING FOR CLINICAL TRIALS The design of clinical trials that are intended to mea- sureshort-termchangesincognitivefunctionshouldbe relatively simple; standard, parallel group or crossover designs. The latter may be particularly appealing in early, learning phase trials, because of the reduc- tion in variability (which allows much smaller sample sizes) due to within-subject comparisons. Crossover designs have their own challenges (e.g., loss to fol- low up, sequence effects), but may still be useful in the early evaluation of agents intended to improve cognitive performance. On the other hand, assessing long-term change in cognitive performance, such as slowing cognitive decline or preventing the onset of dementia (i.e., disease-modifying effects), present a major design challenge, and biomarkers could play a critical role in such studies. It is premature to rec- ommend specific biomarkers but ongoing research should help to determine those that are most useful and could include imaging (positron emission tomography and fluorodeoxyglucose, functional MRI, amyloid, and hopefully eventually alpha-synuclein) and cere- brospinal fluid, blood and genetic markers, the subject of a recent review [23]. As disentangling short-term improvements from long-term effects is difficult, a two-period design (e.g., delayed start or washout) can be considered. There are many inherent complexities in such designs (as seen with the ADAGIO study), [24] including the duration of the two study periods, avoid- ing dropouts, and methods to analyze the stability of differences observed at study completion. An attractive alternative may be a survival analysis, such as delay of time to onset of dementia or cognitive impairment. The main challenge of such ‘survival’ studies will be a rigorous, yet pragmatic, definition of these endpoints. Given the novel nature of this therapeutic endpoint, discussions of trial design with regulatory authorities in advance of the study will be essential. THE CURRENT THERAPEUTIC LANDSCAPE Many of the therapeutics that have been tested for PD-MCI and PDD are those that have been tested
  • 4. 588 J. Eberling et al. / Therapeutic Development Paths for PD-MCI Box 1. Path Forward for Cognitive Impairment in PD General Path Forward • The FDA is open to an indication for mild cognitive impairment in PD • For regulatory consideration, it may be appropriate to pursue a PD-MCI indication without reference to the underlying cause of impairment • Drug approvals for an indication of PD-MCI will likely require a co-primary measure (a cognitive outcome measure and a functional measure) Short Term Path: Long Term Path: For immediate drug development using existing scales and diagnostic criteria Includes efforts to validate diagnostic criteria and/or create new instruments Diagnostic Criteria Diagnostic Criteria • Current MDS PD-MCI diagnostic criteria can be used to identify a patient population for clinical testing • If a sponsor chooses not to use the criteria, they must demonstrate that the study participants have a cognitive deficit • MDS will work to validate and modify the PD-MCI diagnostic criteria (where needed) so the field can have a standardized approach for identifying and classifying study participants Outcome Measures Outcome Measures • Existing cognitive scales are sufficient for use in clinical trials on PD-MCI • Sponsors should select the outcome measure/scale most likely to demonstrate change in the patient population • The scale does not have to be specific to Parkinson’s nor does it need to be an established measure of response to treatment • The field should work at analyzing PD-MCI datasets across a number of research studies in order to identify the scale items and domains most sensitive to change • If the existing scale instruments, either cognitive of functional, prove to be sub-optimal in clinical testing, the PD field could develop a new scale or a composite measure • In addition to a cognitive scales, sponsors will be required to include a measure of function to demonstrate clinical meaningfulness Biomarkers • The field should work toward the development of an imaging, fluid, or combination biomarker for MCI and AD, including cholinesterase inhibitors and memantine. This seems a reasonable strategy given the overlap in many of the cognitive symptoms although to date rivastigmine is the only approved drug for PDD, albeit modestly effective. Thera- peutics currently being tested for PD-MCI include rasagiline, rivastigmine, droxidopa, and AVE8112, a PDE4 inhibitor (see clinicaltrials.gov NCT01723228, NCT01519271, NCT02066571, NCT01803945). In addition to pharmacological interventions, nonphar- macolocial interventions such as cognitive training, exercise programs, and brain stimulation techniques are being explored [25–27]. While this is a growing area of research there is a need for rigorous studies with appropriate control groups to definitively test these approaches. A clear regulatory path with established diagnostic criteria and outcome measures would likely increase interest in developing PD-MCI therapies. THE PATH FORWARD The pursuit of disease-modifying therapies for neu- rological diseases, including PD, is the ultimate goal for drug developers in this therapeutic space, but the regulatory requirements for FDA approval and the expense and complexities of such clinical trials rep- resent very high hurdles. Given the challenges in pursuing a disease-modifying approach for cognitive impairment, symptomatic therapies may represent an attractive way to move the path forward for drug devel- opment in PD-MCI at this point, and some of these may also prove to delay the time from PD-MCI to dementia. Symptomatic trials could be advantageous given their shorter duration compared with disease-modifying tri- als. Disease-modifying therapies, albeit likely more challenging to develop since requiring longer trials and more complicated study designs, remain the “holy grail”, as they have the potential to impact on disease course. Slowing the progression of cognitive decline and thus forestalling or preventing the development of dementia would represent a tremendous advance in the management of patients with PD. The challenges posed do not mean that disease modification is not worth pursuing, but rather that symptomatic therapies may represent an easier initial target for advances in PD-MCI treatments. The good news is that there is a path forward for therapeutic development for cognitive impairment in PD, though this path will likely continue to be mod- ified as we advance our understanding of PD-MCI as a syndrome. In pursuit of drug development or clini- cal testing, the field will need to address the following challenges: [1] refining and validating the diagnostic criteria in order to identify the patients who are most likely to benefit from treatment, [2] understanding the prognostic significance of PD-MCI, including the tra- jectory of cognitive decline, [3] further developing cur- rent instruments, including those to measure functional
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