Clinical research for neuropathies

Journal of the Peripheral Nervous System 17(Supplement):40-42 (2012)
REVIEW
Clinical research for neuropathies
Petra Kaufmann
National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Abstract The National Institutes of Health (NIH) has a long-standing commitment to
neuropathy research. From 2005-2009, the NIH has committed US $115 million each year.
A collaborative effort between researchers and patients can accelerate the translation of
pre-clinical discoveries into better treatments for neuropathy patients. Clinical trials are
needed to test these new treatments, but they can only be implemented in a timely
fashion if patients with neuropathies are willing to participate. This perspective focuses
on the value of having various outlets for informing both the patients and the physicians
about existing clinical research opportunities and on the potential benefit of establishing
patient registries to help with trial recruitment. Once data have been collected, there is a
need to broadly share the data in order to inform future trials, and a first step would be to
harmonize data collection by using Common Data Elements (CDEs).
Key words: clinical research, clinical trials, data sharing, neuropathy, research infrastructure
Although there has been great progress in our
enrollment. This is in part due to lack of information
understanding of the biology of the neuropathies,
among patients and health care providers as to the
there remains room for improved therapeutics. For
critical role that clinical research plays in getting
many sporadic neuropathies, there is a need for
new and more effective therapeutics to patients.
neuroprotective treatments and for symptomatic
Research in a motor neuron disorder suggests that
treatments that have a more favorable side effect
the most common reason for non-participation in
tolerability and benefit profile than the existing choices.
research is the lack of information on clinical research
For the hereditary neuropathies, there is a paucity of
in general, but also on specific trial opportunities.
choices, and a great unmet need. In addressing this
Patient voluntary organizations can play an important
gap between scientific progress and its translation into
role in informing their constituency on the importance
better therapeutics, clinical research plays an important
of clinical research and on alleviating some commonly
role. To increase the success of clinical research and
cited concerns over risks privacy and costs associated
accelerate the clinical research process, the following
with research participation (Bedlack et al., 2007). It is
issues should be considered:
also important that organizations interested in better
therapeutics for neuropathies encourage physicians,
both specialists and general health care providers,
Encouraging Patient Participation
to make a discussion of clinical research opportunities
in Clinical Research
part of every neuropathy-related health care encounter.
Many clinical research studies take too long or
In addition to print materials such as newsletters, there
even fail to complete due to very slow participant
are now new web-based opportunities through email
lists and social media.
For the types of hereditary neuropathies that are
Address correspondence to: Petra Kaufman, MD, MSc, Associate
considered rare diseases, information alone may not
Director of the Office of Clinical Research, National Institute of
overcome the barriers to recruitment. It may be
Neurological Disorders and Stroke, 6001 Executive Blvd., NSC,
necessary to establish registries with the goal of
Room 2216, Bethesda, MD 20892-9520, USA. Tel: +1 301-496-
9135; Fax: +1 301-480-1080; E-mail: petra.kaufman@nih.gov
recruiting patients into clinical trials. In other disease
Published 2012. This article is a U.S. Government work and is in the public domain in the USA.
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Kaufmann
Journal of the Peripheral Nervous System 17(Supplement):40-42 (2012)
areas, for example Friedreich's ataxia, these kinds
However, natural history studies are at times not
of registries have resulted in the full enrollment of
conducted with a therapeutics development perspec-
participants into clinical trials in very short time periods
tive in mind. The quality of data and completeness
(http://www.curefa.org/registry/).
of follow-up are important characteristics that make
a natural history dataset suitable for clinical trial
planning. Certain outcome measures or biomarkers
Strengthening the Clinical Research
may be of great academic interest, but may not
Workforce for Neuropathies
represent a path forward for therapeutics develop-
ment, that is, if they are not transferable to the
Implementing a clinical research study requires
multiple sites of a typical clinical trial, or if they are
special training and skills beyond scientific knowledge.
not meeting the expectations of regulatory agencies
These skills are of a logistical and organizational nature.
such as the Food and Drug Administration (FDA)
In addition, expertise in regulatory affairs and statistical
(www.fda.gov/downloads/Drugs/GuidanceCompliance
design is required. As these skills are often not
RegulatoryInformation/Guidances/UCM267449.pdf).
sufficiently taught in the medical establishment, skilled
Similarly, researchers often engage in efforts to
clinical researchers are rare. To ensure a sufficient
improve outcome measures without thinking of a
workforce going forward, it is therefore important that
regulatory pathway, a must if an outcome is to
stakeholders in neuropathy clinical research join forces
be used in the testing of new therapeutics. For
in training the next generation of clinical researchers
regulatory purposes, it is important that an out-
by including new investigators into clinical research
come be clinically meaningful and measure a con-
projects and by providing pilot or career development
cept that is important to patients with the disease.
funding opportunities for new clinical researchers who
Patient-reported outcomes, or outcomes that reflect
are interested in neuropathies.
how a patient feels and functions, are of particu-
lar interest, and the FDA has issued guidance as
to the development of patient-reported outcomes
Harmonizing Data Collection for Future
(www.fda.gov/downloads/Drugs/GuidanceCompliance
Data Sharing
RegulatoryInformation/Guidances/UCM193282.pdf).
It is very costly and labor intensive, both for
The NIH has launched two inter-related initiatives:
patients and investigators, to gather clinical research
PROMIS: Patient-Reported Outcomes Measurement
data. However, many neuropathy datasets probably
Information System (http://www.nihpromis.org/) and
never fully materialize their value because the data
NeuroQoL: Quality of Life Outcomes in Neurologi-
are collected in different ways for each project. The
cal Disorders (http://www.neuroqol.org/default.aspx).
multiple different data standards and outcomes that
Both initiatives are item banks with the goal to assist
are collected make it difficult to share data or to
investigators in collecting patient reported outcomes.
combine datasets for meta-analysis and trial planning.
The item banks can be used through traditional paper
It would therefore be an advantage toward accelerating
forms, or through computer-assisted testing. They are
clinical research if neuropathy investigators were
available online, and designed to be used across the
to collect a core set of variables, and were to
lifespan, from pediatric to adult patients. In contrast,
follow uniform or harmonized data standards. Also,
there is also a need for consensus on the use of com-
research could be accelerated if those data were
mon outcome measures between investigator groups.
shared soon after the data collection and made
The need for innovation in outcome measures has to
available to other investigators. The NINDS has created
be weighed against the advantages of consistency. If
Common Data Elements (CDEs), that is, publicly
each investigator group examines different outcomes,
available data standards for clinical research into
data cannot be compared and combined.
neurological disease, some of which may be useful in
neuropathy trials (http://www.commondataelements.
ninds.nih.gov/).
Coordinating Between Stakeholders,
in the United States and Abroad
Strategically Planning Research on the
The coordination between stakeholders is a
Natural History, Biomarkers, and Clinical
key
factor
in
accelerating
the
development
of
Outcomes
new therapeutics. There are several very valuable
partnerships that should be considered. First, the
To plan clinical trials, it is essential that high
partnership between investigators and patients is often
quality and recent natural history data are available.
the key to downstream success in clinical research
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Kaufmann
Journal of the Peripheral Nervous System 17(Supplement):40-42 (2012)
implementation. If patients have input into which
to facilitate the implementation of protocols in this
research questions matter and should be addressed,
disease
(http://rarediseasesnetwork.epi.usf.edu/INC/
then there will likely be more patient participation
about/index.htm). One important feature of these net-
in the resulting trial. Also, investigators can partner
works is the engagement of patient groups at all levels,
with patients in protocol development, because who
from the concept of studies to ongoing representa-
can better advise on the length and number of visits
tion on the steering committee. Since disease-specific
or protocol burden than patients and their families.
networks are often not available, neuropathy investi-
Patients can also be involved in reviewing consent
gators can explore networks with a broader scope.
forms or communications plans with regards to the
One such network is the Network for Excellence
research results. One common fallacy, in particular
in Neuroscience Clinical Trials (NeuroNEXT), a clini-
with rare disease where there is a large unmet medical
cal research network designed to accelerate therapy
need, is the therapeutic misconception. This can
development. NeuroNEXT was created with three
arise when the premise of the trial is misunderstood
main goals in mind: (1) to support scientifically valid,
and when the new intervention is believed to be
biomarker-informed phase 2 (exploratory) clinical trials
beneficial when, in reality, the evidence is still pending.
that can efficiently test new treatments before embark-
This leads to disappointment when an initial trial is
ing on large phase 3 (efficacy) trials; (2) to expand
negative - as most trials are in the history of medicine.
the ability to test the most promising new thera-
It is therefore very important that the premises of a
pies, whether from academic or industry investigators;
trial and the results are communicated in a careful and
and (3) to provide the infrastructure for and exper-
patient-oriented manner.
tise of a cadre of disease-specific investigators, as
Second, partnership between investigators, in the
trial opportunities arise for a wide range of disorders
United States and abroad, is key to ensuring success
affecting both children and adults. NeuroNEXT has
of clinical trials. It is very important that efforts are not
some novel features designed to increase the effi-
duplicated in different countries, given that resources
ciency and shorten the start-up time of trials, including
for clinical research are limited and patient pools
the use of a central IRB of record to avoid the redun-
are finite, in particular for hereditary neuropathies.
dancy of repeated reviews at multiple sites, and the
Rather, a well-coordinated effort can allow synergistic
use of master trial agreements to avoid delays arising
contributions toward a common goal: to accelerate
from subcontract negotiations in clinical trials. The
clinical research for the neuropathies.
25 network sites, a clinical coordinating center, and a
Third, partnerships between academic and indus-
data coordinating center have been selected, and the
try investigators are paramount in bringing novel
network is now open to accept applications from aca-
treatments to patients. While there are concerns over
demic investigators, as well as from the biotechnology
potential conflicts of interest, these partnerships are
or industry sector for access to the network infrastruc-
needed because universities and academic investi-
ture (http://www.ninds.nih.gov/NeuroNEXT).
gators cannot ultimately bring new drugs into the
In summary, there is great hope for better
pharmacy by themselves. Therefore, managing any
treatments in the neuropathies given the tremendous
potential conflicts of interest and engaging in private
progress in our understanding of the underlying genetic
public partnerships are important steps toward better
etiology or disease biology. The NINDS and the NIH
therapeutics.
have several programs that the stakeholders can
consider. In addition to the resources described in this
summary, the NINDS staff can work with investigators
Building on Existing Infrastructure
to identify opportunities within the clinical research
programs.
Investigator networks can accelerate therapeu-
tics evaluation. Typically, clinical trials infrastructure is
created de novo for each clinical trial, and then discon-
Disclosure
tinued once a given trial has been completed. Having
a network can save some time in start-up and recruit-
The author declares no conflict of interest.
ment because the investigators already have an estab-
lished infrastructure and collaborations. For one form
of hereditary neuropathies, Charcot-Marie-Tooth dis-
Reference
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and Stroke are funding the Inherited Neuropathies
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Consortium, a clinical research network designed
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